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Marine natural products


John W. Blunt,*a Brent R. Copp,b Murray H. G. Munro,a Peter T. Northcotec and Michele R. Prinsepd
Received 7th November 2010
DOI: 10.1039/c005001f

Covering: 2009. Previous review: Nat. Prod. Rep., 2010, 27, 165
This review covers the literature published in 2009 for marine natural products, with 857 citations (588
for the period January to December 2009) referring to compounds isolated from marine
microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans,
molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The
emphasis is on new compounds (1011 for 2009), together with the relevant biological activities, source
organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the
revision of structures or stereochemistries, have been included.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Introduction
Reviews
Marine microorganisms and phytoplankton
Green algae
Brown algae
Red algae
Sponges
Cnidarians
Bryozoans
Molluscs
Tunicates (ascidians)
Echinoderms
Mangroves and the intertidal zone
Miscellaneous
Conclusion
References

1 Introduction
This review is of the literature for 2009 and describes 1011 new
compounds from 352 articles, a small decrease from the number
(1065) of compounds reported for 2008.1 As in previous reviews,
the structures are shown only for new compounds, or for
a
Department of Chemistry, University of Canterbury, Christchurch, New
Zealand. E-mail: john.blunt@canterbury.ac.nz
b
Department of Chemistry, University of Auckland, Auckland, New
Zealand
c
School of Chemical and Physical Sciences, Victoria University of
Wellington, Wellington, New Zealand
d
Department of Chemistry, University of Waikato, Hamilton, New
Zealand
This paper is part of an NPR themed issue on Marine Natural
Products.

196 | Nat. Prod. Rep., 2011, 28, 196268

previously reported compounds where there has been a structural


revision or a newly established stereochemistry. Previously
reported compounds for which first syntheses or new bioactivities are described are referenced, but separate structures are
generally not shown. Where the absolute configuration has been
determined for all stereocentres in a compound, the identifying
diagram number is distinguished by addition of the symbol. In
the previous review,1 a new section describing compounds from
mangroves and other intertidal species was introduced. That
section included compounds from microorganisms isolated from
mangroves and other sources in the intertidal zone. For consistency, all reports for microorganisms from that region will now
appear in the Marine microorganism and phytoplankton
section of this review. In compiling this review, large differences
were noted in the detail with which the geographic location and
taxonomy of the field samples were recorded. As regards location, these ranged from highly specific with GPS coordinates to
source not given or just a wide geographical area such as South
Pacific. For taxonomy there were variations ranging from full
genus/species description to unidentified species. In one classic
example, which has reluctantly been included in this review, it
was unidentified marine fungus, source not given. The requirements of the leading journals in the field of natural products are
quite specific and unless full descriptors are provided, the paper
will not be considered for publication. In this electronic age there
is no reason not to have an exact description of the location, and
with the molecular biology tools now readily available, assignment at the genus level is usually attainable. To ensure that the
reporting of marine natural products research is carried out with
the highest possible accuracy, it would be very desirable to get
away completely from the unidentified marine fungus, source not
given descriptor. There are guidelines available: as a reader of
this review you may also be a reviewer of manuscripts if not
now, perhaps in the future. It would be helpful to the marine
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natural products community and to the Editors if such glaring


discrepancies were pointed out in any papers you might referee.

John Blunt

John Blunt obtained his BSc


(Hons) and PhD degrees from
the University of Canterbury,
followed
by
postdoctoral
appointments in Biochemistry at
the University of Wisconsin
Madison, and with Sir Ewart
Jones at Oxford University. He
took up a lectureship at the
University of Canterbury in
1970, from where he retired as
an Emeritus Professor in 2008.
His research interests are with
natural products, and the application of NMR techniques to
structural problems.

Brent Copp received his BSc


(Hons) and PhD degrees from
the University of Canterbury,
where he studied the isolation,
structure elucidation and structureactivity relationships of
biologically
active
marine
natural products under the
guidance of Professors Blunt
and Munro. He undertook
postdoctoral research with Jon
Clardy at Cornell and Chris
Ireland at the University of
Brent Copp
Utah. 199293 was spent
working in industry as an isolation chemist with Xenova Plc,
before returning to New Zealand to take a lectureship at the
University of Auckland, where he is currently an Associate
Professor.
Murray Munro, now an Emeritus Professor at the University
of Canterbury, Christchurch,
New Zealand, worked on
natural products, mainly of New
Zealand origin, right through his
career. This started with diterpenoids (PhD), followed by
alkaloids during a postdoctoral
spell with Alan Battersby at
Liverpool. Following a sabbatical with Ken Rinehart at the
University of Illinois in 1973, an
Murray Munro
interest in marine natural products developed with a particular
focus on bioactive compounds.
In recent years his research interests have widened to include
terrestrial and marine fungi and actinomycetes as well as marine
invertebrates.
This journal is The Royal Society of Chemistry 2011

Reviews

A comprehensive review of marine natural products reported in


2007 has appeared,2 as well as the highlights of compounds
reported in 2008.3 A focus on drug development and pharmacology of marine natural products has been described in several
reviews.48 Reviews on more specific types of biological activities
include antimalarials,912 antitumour compounds1319 and antifoulants.20,21 Specific compounds that were reviewed include the
halichondrins,22 variolins,23 aplysinopsins,24 and aplyronine A,25
while more general classes of compounds such as sterols from soft
corals,26 aziridine alkaloids,27 benzothiazole alkaloids,28 muscarine, imidazole, oxazole and thiazole alkaloids,29 ribosomal
peptides,30 phospholipids,31 terpenyl-purines,32 non-methyleneinterrupted fatty acids,33 molluscan antimicrobial peptides,34
indole alkaloids with a non-rearranged monoterpenoid unit,35
diterpenes from gorgonians,36 sesquiterpenoids,37 diterpenoids,38
verticillane derivatives,39 2,11-cyclised cembranoids from the
Caribbean40 and siderophores were reported.41,42 Conotoxins and
Peter Northcote received his
BSc and PhD degrees from the
University of British Columbia,
Canada, where he was a member
of R. J. Andersens marine
natural products research group.
He carried out postdoctoral
research with Professors Blunt
and Munro at the University of
Canterbury
before
taking
a position as a senior research
scientist at Lederle Laboratories, American Cyanamid Co.
Peter Northcote
He joined the faculty of the
Victoria University of Wellington in 1994, where he is currently an
Associate Professor in organic chemistry.

Mich
ele Prinsep received her
BSc (Hons) and PhD degrees
from the University of Canterbury, where she studied the
isolation and structural elucidation of biologically active
secondary metabolites from
sponges and bryozoans under the
supervision of Professors Blunt
and Munro. She undertook
postdoctoral research on cyanobacteria with Richard Moore at
the University of Hawaii before
Michele Prinsep
returning to New Zealand to
take up a lectureship at the University of Waikato, where she is
currently a Senior Lecturer.
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other peptide toxins continue to be reviewed extensively.4349


Compounds from particular types of organism were covered in
reviews on Sinularia spp.50 semi-mangroves,51 bacteria5254 and
sponges,55,56 while the chemistry and biology of some Okinawan
marine natural products have been described.57 The methods for
study, structural types and biological properties of the fucoidans
have been summarised.58 There has been a commentary on
spongemicrobial symbioses.59 Various aspects of the biosynthesis of marine natural products have been reviewed.6063 The
fifth in a companion series providing an overview of synthetic
aspects of marine natural products, covering publications in 2007,
has appeared,64 while more specific reviews that appeared in 2009
relating to the synthesis of marine natural products will be
referenced in the seventh of that broad review series. Recent
synthetic studies leading to structural revision of marine natural
products have been collated.65 The MarinLit database66 has been
updated and was used as the literature source for the preparation
of this present review.

olide CE, which were most likely artefacts. Marinisporolide A 1


had modest activity against Candida albicans.67
Culture of Saccharomonospora sp. [sediment, (La Jolla, California)] yielded the alkaloid lodopyridone 3 with a unique
carbon skeleton and modest cytotoxicity to HCT-116 cells.68 An
angucyclinone 4, isolated from culture of Saccharopolyspora
taberi, [sponge, (Tanzanian coast, Africa)], was active against
a selection of human cancer cell lines.69
Of the arenamides AC 57 from Salinispora arenicola [sediment, (Great Astrolabe Reef, Fiji)], 5 and 6 blocked tumour
necrosis factor (TNF)-induced activation, inhibited nitric oxide
and prostaglandin E2 production and were moderately cytotoxic
to HCT-116 cells.70 Culture of S. arenicola [sediment, (Yap,
Micronesia)] yielded the rifamycin antibiotic salinisporamycin 8,
which inhibited growth of A549 cells and displayed activity
against Bacillus subtilis and Staphylococcus aureus.71

3 Marine microorganisms and phytoplankton


Microorganisms of marine origin continue to be a rich source of
novel and/or biologically active metabolites, with 273 new
compounds reported in 2009. Marinisporolides A 1 and B 2 are
polyene macrolides isolated from culture of an actinomycete
from the new genus Marinispora [sediment, (La Jolla, California)]. Under ambient light conditions marinisporolides A 1
and B 2 photoisomerised to the geometric isomers marinispor-

Antiprotealide, described previously as a synthetic


compound,72 was isolated as a natural product from a large-scale
fermentation of S. tropica.73 Culture of Bacillus pumilus [sediment, (Bahamas)] yielded lipoamides AC 911, in addition to
known compounds, of which amicoumacin A74 had activity
against methicillin-resistant Staphylococcus aureus (MRSA).75

Bacillistatins 1 12 and 2 13 are cyclodepsipeptides from


Bacillus silvestris [Pacific Ocean crab, (Quellon, Chiloe Is.,
Chile)] and were strongly inhibitory against a number of human
cancer cell lines and active against Streptococcus pyrogenes and
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antibiotic-resistant S. pneumoniae.76 Bacillistatin 2 13 was synthesised via a 24-step convergent route utilising the Mitsunobu
reaction.77

Culture of B. vallismortis [Dysidea avara, (Sanya Is., South


China Sea)] yielded a thiazole alkaloid, neobacillamide A 14.78
6-Hydroxymethyl-1-phenazine-carboxamide 15 and 1,6-phena-

zinedimethanol 16, isolated from Brevibacterium sp. [purple vase


sponge Callyspongia sp., (Kyung-po, S. Korea)], exhibited potent
activity against Enterococcus hirae and Micrococcus luteus.79
Scale-up of a culture of Hahella chejuensis [sediment, (Gejae Is.,
S. Korea)], source of chejuenolides A and B,80 gave a 17membered cyclic polyene, chejuenolide C 17.81
The amphiphilic siderophores loihichelins AF, 1823, were
isolated from Halomonas sp. (Loihi seamount, Hawaii).82
Culture of Microbulbifer sp. [calcareous sponge Leuconia nivea,
(Concarneau, France)], yielded natural parabens. Of these, 2427
were new with bacteriocidal or bacteriostatic properties, while
the known octyl,83 decyl84 and dodecylparabens85 were isolated
for the first time as natural products.
Culture of the myxobacterium Nannocystis exedens [sand,
(Crete)] yielded phenylnannolones AC 2830. Phenylnannolone
A 28 inhibited P-glycoprotein and reversed daunorubicin resistance in A2780 ovarian cancer cells. Biosynthetic studies of 28
indicated a polyketide origin with a phenylalanine-derived
starter unit of novel biosynthetic origins.86 All of the indoxamycins AF, 3136, unusual polyketides with six consecutive
chiral centres isolated from Streptomyces sp. [sediment, (Kochi
Harbour, Japan)], were moderately cytotoxic to HT-29 cells.
Biosynthetic-feeding experiments indicated that indoxamycin A
31 was assembled from propionate units which initially formed
a pentamethylindenofuran.87

Ammosamides A 37 and B 38 are chlorinated tricyclic pyrroloquinoline alkaloids from Streptomyces sp. [sediment, (Bahamas)]. Ammosamide A 37 contains an unusual thio-g-lactam
ring and gradually converted to ammosamide B 38 on exposure

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to air. Both 37 and 38 displayed potent cytotoxicity against


a number of cancer cell lines. The target was identified as the
motor protein, myosin.88,89 Splenocins AJ 3948 are ninemembered bis-lactones isolated from Streptomyces sp. [sediment,
(La Jolla, California)] with potential for development for asthma
treatment, due to suppression of cytokine production with
minimal mammalian cell cytotoxicity.90 Culture of Streptomyces
sp. [sediment, (Atlantic Ocean)] resulted in isolation of albidopyrone 49, a moderate inhibitor of protein-tyrosine phosphatase
B.91

Mansouramycins AD 5053 are isoquinolinequinones


obtained from culture of Streptomyces sp. [mud, (Jade Bay,
German North Sea Coast)]. A related compound, 3-methyl-7(methylamino)-5,8-isoquinolinedione of synthetic origin,92 was
isolated for the first time. Mansouramycin A 50 was moderately
active against S. aureus, B. subtilis and E. coli and a strong
inhibitor of the microalgae Chlorella vulgaris, C. sorokiniana and
Scenedesmus subspicatus. All isolated compounds exhibited high
cytotoxicity when tested in a panel of 36 tumour cell lines, with
several showing high selectivity.93

Fermentation of Streptomyces sp. [sediment, (Madagascar)]


gave tartrolon D 54 which was strongly cytotoxic to A549, HT29 and MDA-MB-231 cells,94 while naseseazines A 55 and B 56,
diketopiperazines with a new dimeric framework, were isolated
from culture of Streptomyces sp. [sediment, (Fiji)].95
Culture of another Streptomyces sp. [sediment, (Miyazaki
Harbor, Japan)] gave two trialkyl-substituted aromatic acids,
lorneic acids A 57 and B 58. Both inhibited human platelet
phosphodiesterase 5 (PDE5), but 57 was the stronger inhibitor.96
Tirandamycins C 59 and D 60 are dienoyl-tetramic acids isolated from fermentation of Streptomyces sp. [sediment, (Salt Cay,
200 | Nat. Prod. Rep., 2011, 28, 196268

Virgin Islands)] along with the previously identified compounds


tirandamycin A97 and B.98 This represented the first marine
isolation of tirandamycins A and B. All metabolites displayed
activity against vancomycin-resistant Enterococcus faecalis
(VRE) with varying degrees of potency.99

Culture of Streptomyces sp. [sand, (Qingdao coast, China)]


yielded two new sesquiterpenes, 15-hydroxy-T-muurolol 61 and
11,15-dihydroxy-T-muurolol 62. The absolute configurations of
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a number of sesquiterpenes isolated previously from the same


strain and reported as amorphanes100 have now been revised to
those of the muurolane series, namely 6366. T-muurolol101 and
3a-hydroxy-T-muurolol,102 known cadinenes from plants, were
isolated from a marine source for the first time.103

The polyketides phaeochromycins FH, 6769, were obtained


from Streptomyces sp. [sediment, (West Pacific Ocean)],104 while
ammonificins A 70 and B 71, both hydroxyethylamine chroman
derivatives, were isolated from Thermovibrio ammonificans
[hydrothermal vent, (East Pacific Rise)].105

and 77115 and a glycoside very similar to 76, but with a rearranged isoprene unit,116 have been previously isolated as plant
metabolites.

Fermentation of Aigialus parvus [mangrove wood (species and


source not given)] resulted in the isolation of the nonaketide
metabolites, aigialomycin F 78 and G 79, 80, 70 ,80 -dihydroaigialospirol 81, 40 -deoxy-70 ,80 -dihydroaigialospirol 82 and
rearranged macrolides 83 and 84. Aigialospirol, previously
described from the same species,117 was reisolated and the
previously suggested absolute configuration confirmed as 85.
Fermentation of Acremonium sp. [sponge, Stelletta sp., (Jeju
Is., S. Korea)], yielded four new sesquiterpenoids including the
chlorinated merosesquiterpenoid chlorocylindrocarpol 72, two
cyclic merosesquiterpenoids, acremofuranones A 73 and B 74,
and dihydrobergamotene 75.

A number of known sesquiterpenoids were also isolated


including lignoren,106 cylindrocarpol,107 ascofuranone,108 ascofuranol,109 ascochlorin,110 cylindrol B,111 ilicicolin F,111
dechloroilicicolin C,111 ilicicolin C111 and deacetylchloronectrin,112 all of which were isolated from the marine
environment for the first time.113 Glycosyl benzenediols 76 and
77 were isolated from culture broth of Acremonium sp. [Demospongiae sponge, (Ishigaki Is., Okinawa)].114 The aglycon of 76
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The known terrestrial fungal metabolite 4-O-demethylhypothemycin118 was isolated from the marine environment for the
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first time.119 Two new perylene derivatives, 7-epi-8-hydroxyaltertoxin I 86 and 6-epi-stemphytriol 87, were isolated from
culture of Alternaria alternata, [Laurencia sp., (Weizhou Is.,
South China Sea)].120
Alternaria raphani [sediment, sea salt field, (Qingdao, China)]
yielded three cerebrosides, alternaroside AC 8890 and a diketopiperazine alkaloid, alternarosin A 91,121 while alternaramide
92, a cyclic pentadepsipeptide, was isolated from culture of
Alternaria sp. [sediment, (Masan Bay, S. Korea)].122
Five cytochalasins, Z16Z20 9397, were isolated from Aspergillus flavipes [inner bark of the mangrove Acanthus ilicifolius,
(Dongzhai Gang, China)]. The known fungal metabolite rosellichalasin123 was also isolated.124

Fermentation of Aspergillus aculeatus [Xestospongia testudinaria, (Ton Sai Bay, Phi Phi Islands, Thailand)] resulted in the
isolation of the tyrosine-derived aspergillusol A 98, which
selectively inhibited a-glucosidase from Saccharomyces cerevisiae. A methyl ester of 4-hydroxyphenylpyruvic acid oxime,
a known synthetic compound,125 was also isolated, but may be
an artefact derived via methanolysis of 98 during isolation.126
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Iso-a-cyclopiazonic acid 99, isolated from Aspergillus flavus


[green alga Enteromorpha tubulosa, (Putian Pinghai, China)], was
modestly cytotoxic to several human tumour cell lines.127

A new gliotoxin analogue, 100, was isolated from Aspergillus


fumigatus [sediment, (Jiaozhou Bay, Qingdao, China)].128
Fermentation of Aspergillus insuetus [Petrosia ficiformis, (Punta
de Santa Ana, Blanes, Spain)] yielded the meroterpenoids terretonin E 101 and F 102, and the known fungal metabolite
aurantiamine,129 isolated from a marine source for the first time.
All were inhibitors of the mammalian mitochondrial respiratory
chain.130 A benzodiazepine analogue, 2-hydroxycircumdatin C
103, was isolated from Aspergillus ochraceus [brown alga
Sargassum kjellmanianum, (Dalian coastline, China)]. In
addition, the known synthetic compound, (11aS)-2,3-dihydro-7methoxy-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)dione131 was isolated from a natural source for the first time.
2-Hydroxycircumdatin C 103 exhibited significant 1,1-diphenyl2-picrylhydrazyl (DPPH) radical-scavenging activity.132

A heptacyclic alkaloid, 21-hydroxystephacidin 104, was isolated from Aspergillus ostianus [unidentified sponge, (Pohnpei)],133 while investigation of Aspergillus sclerotiorum [Mycale
sp., (Ishigaki Is., Okinawa)] gave N-demethyl aspochracin 105.134
The cyclic hexapeptides sclerotide A 106 and B 107 were isolated from A. sclerotiorum [Putian Sea Salt Field, (Fujian,
China)] in a nutrient-limited hypersaline medium. Sclerotides A
106 and B 107 were photo-interconvertible. Both 106 and 107
displayed moderate activity against C. albicans, and 107 was
weakly cytotoxic to HL-60 cells and inhibited P. aeruginosa
growth.135

Investigation of Aspergillus terreus [Sinularia kavarattiensis,


(Mandapam, India)] led to the aromatic butenolides aspernolide
A 108 and B 109. Aspernolide A 108 was first reported as
a reaction product in the structural elucidation of the parent
acid136 from a terrestrial strain of A. terreus, but this is the first
report from a marine source. Aspernolide B 109 and a known coisolated butyrolactone I137 (but here called aspernolide C) were
unstable, and on storage converted to aspernolide A 108.138

Seven drimane sesquiterpenoids 110116 were isolated from


the culture broth of A. ustus [Suberites domuncula, (Adriatic
Sea)]. Compounds 113 and 114 and the co-isolated, known sesquiterpenoid RES-1149-2139 were cytotoxic to several tumour cell
lines.140 This was the first marine isolation of sesquiterpene RES1149-2.139
Published almost simultaneously with the previous report140
were details of three drimane sesquiterpenes (ustusols AC 110,
117 and 118), five drimane sesquiterpene esters (ustusolates AE
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Culture of Aspergillus sp. [seawater, (Quan-Zhou Gulf,


China)] yielded asperxanthone 129 and asperbiphenyl 130,
inhibitors of Tobacco Mosaic Virus (TMV) replication.142 The
amide alkaloids 131 and 132 were characterised from an
unidentified endophytic fungus [mangrove, Acanthus ilicifolius,
(South China Sea)].143

119122 and 114), and six benzofuran derivatives (ustusoranes


AF 123128) from Aspergillus ustus [rhizosphere soil of the
mangrove Bruguiera gymnorrhiza, (Wenchang, Hainan Province,
China)].141 Ustusol A and ustusolate E were identical to two of
the compounds 110 and 114 in the previous report.140 Ustusorane
E 127 displayed strong growth inhibition of HL-60 cells, ustusolates C 121 and E 114 exhibited moderate growth inhibition of
A549 and HL-60 cells, and ustusolate A 119 showed weak
growth inhibition of HL-60 and A549 cells.141

The alkaloid cottoquinazoline A 133 and the cyclopentapeptides, cotteslosin A 134 and B 135 were isolated from
Aspergillus versicolor [sand, (Cottesloe, Western Australia)].144

Culture of Aspergillus sp. [Mytilus edulis, (Noto Peninsula, Sea


of Japan)]145 gave notoamide E 136 which had previously been
proposed146 as an advanced precursor to notoamides AD145 and
synthesised,146 but had not been isolated. Biosynthetic studies of
the producing organism indicated that notoamide E 136 was
a short-lived metabolite and feeding experiments utilising
synthetic, 13C-labelled 136 showed incorporation into notoamides C,145 D145 and 3-epi-notoamide C.146 These studies also
produced three minor new alkaloids notoamides E2E4 137
139.147
The same culture of Aspergillus that yielded notoamides A
D145 was then further investigated and notoamides LN 140142,
and antipodal ()-versicolamide B isolated. (+)-Versicolamide B
had previously been isolated from a terrestrial species.148 This
example, along with (+)-148 and ()-notoamide B145 and (+)145
and ()-stephacidin A,148 led to a plausible biosynthetic pathway
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involving a stereoselective indole oxidase.149 Asymmetric total


syntheses of both antipodes of versicolamide B have been achieved, utilising an intramolecular hetero-DielsAlder reaction as
a key step.150
Aureobasidin 143, an ester with an unusual 4,6-dihydroxydecanoic acid residue, was isolated from culture of Aureobasidium
sp. [seagrass,
Poseidonia oceanica,
(Moraira,
Mediterranean Sea, Spain)] along with the known Aureobasidium
metabolite, 3,5-dihydroxydecanoic acid.151 Both compounds
inhibited growth of B. subtilis, E. coli and S. aureus.152 Culture of
Beauveria bassiana [sponge, Myxilla incrustans, (Helgoland Is.,
Germany)] led to the moderately cytotoxic tetramic acid derivative, beauversetin 144.153 The known tetramic acid derivative

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Sch210972154 was isolated from the marine environment for the


first time from Microplodia sp. [green alga, Enteromorpha sp.,
(Fehmarn Is., Baltic Sea)] and was an inhibitor of human
leukocyte elastase (HLE) with moderate activity against Bacillus
megaterium.153
Culture of Chaetomium globosum, originally isolated from
a fish [Mugil cephalus, (Katsuura Bay, Japan)], and which had
earlier yielded the azaphilones chaetomugilins AF,155,156 resulted in isolation of further members of the series, chaetomugilins
G 145 and H 146,157 IO 147153158 and seco-chaetomugilins A
154 and D 155.159 The known terrestrial fungal metabolite
chaetoviridin C160,161 was also isolated and the absolute configuration established as 156. All of the new chaetomugilins, except
chaetomugilin M 151, were cytotoxic. Chaetomugilin I 147 was
selectively cytotoxic against a panel of 39 human cancer cell
lines.158
A bisdihydroanthracenone derivative (eurorubrin 157), two
seco-anthraquinone derivatives (3,2-O-methyl-9-dehydroxyeurotinone 158 and 4,2-O-methyl-4-O-(a-D-ribofuranosyl)-9-dehydroxyeurotinone 159), and an anthraquinone glycoside (6,3-O(a-D-ribofuranosyl)questin 160), were isolated from Eurotium
rubrum [stem tissue of the mangrove Hibiscus tiliaceus, (Hainan,
Is., China)]. Compounds 158160 displayed modest DPPH
radical-scavenging activity, whilst the previously known co-isolated fungal metabolite 2-O-methyleurotinone162 displayed
strong activity.163
Fusaquinon A 161 is an anthraquinone derivative isolated
from Fusarium sp. [mangrove sediment, (Zhuhai, China).164 Two
further compounds were isolated and designated as fusaquinons
B and C. Seemingly, the enantiomers of these compounds
have been published previously, and were designated tetrahydrobostrycin165 and 1-deoxytetrahydrobostrycin165 respectively,
while an isomer of tetrahydrobostrycin has previously been isolated from the mangrove endophyte Halorosellinia sp.166 by the
same group as this current report. There are, however, discrepancies between the reported optical rotations for the compounds
in all three papers, so the stereochemistries of these compounds
require further clarification.
Two piperazine-2,5-dione derivatives, gliocladride A 162 and
B 163, were isolated from Gliocladium sp. [sea mud, (Rushan,
China)]. Both compounds were moderately cytotoxic to HL-60,
U937 and T47D cells, whilst the co-isolated, known compound,
deoxymycelianamide,167 was strongly cytotoxic to U937 cells.
The name gliocladride was given to a different compound
previously reported by the same authors from the same source,168
but which lacked the C-6C-7 double bond. Gliocladrides A 162
and B 163 are the NOH derivatives of compounds PJ147 and
PJ157 respectively, also previously reported by the same authors
from the same source.169 Inexplicably, none of the earlier work
was cited in this current report.170
Of the nigrosporapyrones AD 164167 isolated from Nigrospora sp. [sea fan, Annella sp., (Similan Islands, Thailand)],
nigrosporapyrone A 164 was moderately active against S.
aureus,171 while Nigrospora sphaerica [intertidal mud, (Nanhai
Sea, China)] yielded 1-(5-oxotetrahydrofuran-2-yl)ethyl 2-phenylacetate 168 and 3-hydroxybutan-2-yl 2-hydroxy-3-phenylpropanoate 169.172
Examination of the culture broth of Paecilomyces lilacinus,
[sponge, Petrosia sp., (Jeju Is., S. Korea)] led to the
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paecilopyrones A 170 and B 171 and the cyclohexenones phomaligol B 172 and C 173.173
Three new breviane spiroditerpenoids, brevione FH 174176,
were obtained from the extreme-tolerant Penicillium sp.
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[sediment from 5115 m, (East Pacific Ocean)], and were moderate


inhibitors of HeLa cells, with brevione F 174 also inhibiting HIV1 replication in C8166 cells. Brevione E174 was also isolated, and
while known from a terrestrial Penicillium sp., was the first
isolation from a marine source.175

A Penicillium sp. [brown alga Xiphophora gladiata, (Macrocarpa Point, New Zealand)] gave the 2-pyridone alkaloids 177
and 178, of which 177 had been previously prepared as a derivative of the co-isolated N-hydroxypyridone antibiotic PF1140.176
This represents the first isolation as a natural product.177 Penicipyrone 179 and penicilactone 180 were isolated from Penicillium sp. [sea fan, Annella sp., (Similan Islands, Thailand)],178
while the sesquiterpenoids JBIR-27 181 and JBIR-28 182 are
eremophilane analogues isolated from Penicillium sp. [ascidian,
Didemnum molle, (Ishigaki Is., Okinawa)]; 182 was moderately
cytotoxic to HeLa cells.179
Kong)] was the source of 7-hydroxyjanthinone 194. This was the
first marine occurence of the co-isolated janthinone,182 a known
metabolite from Penicillium janthinellum found as an endophyte
of Melia azedarach (chinaberry).183 Chromanone A 195 from
a Penicillium sp. [green alga, Ulva sp., (Suez Canal, Egypt)]
possessed a range of biological activities including cytochrome
P450 1A (CYP1A) inhibition, glutathione S-transferases (GST)
and epoxide hydrolase (mEH) induction and potent radicalscavenging activity against hydroxyl radicals.184

Ten new compounds, including the alkaloids meleagrins B 183


and C 184, the diketopiperazine alkaloids roquefortines F 185
and G 186, and the diterpenes conidiogenones BG 187192,
originated from Penicillium sp. [sediment, (5080 m, location not
given]. All compounds were cytotoxic against a panel of four
cancer cell lines, with conidiogenone C 188 potently cytotoxic to
HL-60 and BEL-7402 cells.180
(3R*,4S*)-6,8-Dihydroxy-3,4,7-trimethylisocoumarin 193 was
isolated from culture of an endophytic Penicillium sp. [roots of
the mangrove Bruguiera sexangula, (Qinglan Port, Hainan,
China)] and was moderately active against K562 tumour cells.181
A Penicillium sp. [bark of the mangrove Kandelia candel, (Hong
This journal is The Royal Society of Chemistry 2011

4-Hydroxyphenethyl methyl succinate 196 and 4-hydroxyphenethyl 2-(4-hydroxyphenyl)acetate 197 were obtained from
Penicillium griseofulvum [mangrove, Lumnitzera racemosa,
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(South China Sea)]. Both compounds were moderately active


radical scavengers of the DPPH free radical and 197 was active
against PC-3 prostate cancer cells.185 Coincidentally, 197 was
simultaneously isolated from terrestrial Aspergillus phoenicis as
aspergillol B,186 but confusingly, the name aspergillol had already
been used to designate a different compound isolated from
a marine strain of Aspergillus versicolor.187

The polyketides spartinol AD 198201 came from the endophyte Phaeosphaeria spartinae [Ceramium sp., (North Sea,
B
usum, Germany)].188 Culture of Phoma sp. [sponge Ectyplasia
perox, (Caribbean Sea, Dominica)] led to isolation of the prenylated polyketides epoxyphomalin A 202 and B 203. Both
compounds were active against a panel of 36 human tumour cell
lines but epoxyphomalin A 202, which was extremely potent,
displayed significant selectivity toward 12 of the cell lines and
possessed a unique cytotoxic selectivity pattern as determined by
COMPARE analyses.189

pestalotiopsone AF 210215 and the known 7-hydroxy-2-(2hydroxypropyl)-5-methylchromone,194 originally isolated from


rhubarb. This was the first isolation from a marine source. Pestalotiopsone F 215 was cytotoxic to L5178Y murine cancer
cells.195

Treatment of a culture of Spicaria elegans [sediment, (Jiaozhou


Bay, China)] with the cytochrome P450 inhibitor metyrapone,
initiated production of two deoxy-cytochalasins, 7-deoxy-cytochalasin Z7 216 (modestly cytotoxic) and 7-deoxy-cytochalasin
Z9 217.196
The polyketide ester 204, isolated from Phomopsis sp.
[mangrove, Excoecaria agallocha, (Dong, Hainan, China)], was
cytotoxic to HEp-2 and HepG2 cells.190 Pichia membranificiens
[sponge, Halichondria okadai, (Izu Peninsula, Japan)] was the
source of the indole derivatives 205 and 206, modest DPPH
radical scavengers. Synthesis of 205 indicated that the isolated
natural product was scalemic in a 5 : 8 ratio of (S):(R) enantiomers.191

The alkaloids plectosphaeroic acid AC 207209 were isolated


from Plectosphaerella cucumerina [sediments, (Barkley Sound,
British Columbia)] as inhibitors of indoleamine 2,3-dioxygenase
(IDO). The co-occurring, known terrestrial fungal metabolite
T988 A192 was also isolated from the marine environment for the
first time.193
Culture of Pestalotiopsis sp. [mangrove leaves, Rhizophora
mucronata, (Hainan Is., China)] produced the chromones
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Using the same Spicaria elegans species, but with variation of


the culture conditions in an OSMAC (one strainmany
compounds) approach, the metabolites produced were greatly
altered. These included the moderately cytotoxic spicochalasin A
218, which has a unique pentacyclic ring system, and the aspochalasins MQ 219223.197
Sporothrins AC 224226 were isolated from fermentation of
Sporothrix sp. [bark of the mangrove Kandelia candel, (South
China Sea)]. Sporothrins A and B exhibited moderate cytotoxicity to HepG2 cells, while sporothrin A 224 was a strong
inhibitor of acetylcholinesterase. Based on gene sequencing, it
was deduced that 1,3,6,8-tetrahydroxynaphthalene (T4HN) was
a precursor in the biosynthesis of the sporothrins.198
A new sorbicillinoid, 6-demethylsorbicillin 227, and a new
bisorbicillinoid, 10,11-dihydrobisvertinolone 228, were isolated
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from a Trichoderma sp. [sediment, (Fujian province, China)].


Both exhibited moderate activities against HL-60 cells. A
number of known sorbicillinoids and bisorbicillinoids were also
isolated, some for the first time from the marine environment.199
A new pyranone derivative 229 was isolated from Trichoderma
viride [sponge, Agelas dispar, (Dominica, Caribbean)].200 The
trivial name trichopyrone was proposed for 229 but this name
had already been used to designate a metabolite from a terrestrial
This journal is The Royal Society of Chemistry 2011

fungus.201 Trichoderma atroviride [mangrove root sediment,


Ceriops tagal, (South Sea intertidal zone, China)] was the source
of compounds 230 and 231.202
Asperelines AF 232237 are peptaibols from Trichoderma
asperellum [sediment, (Penguin Is., Antarctica)] which are characterised by an acetylated N-terminus and a C-terminus with the
uncommon prolinol residue. Absolute configurations were
determined via a new method involving direct 1H NMR spectroscopic comparison of the complexes formed between the
chiral reagent Ru(D4-Por*)CO and the amino acids from
hydrolysis of the peptaibols against reference amino acid standards.203 Fermentation of Xylaria sp. [seeds of a mangrove, (Mai
Po, Hong Kong, China)] gave xylopyridine A 238 which had
strong DNA-binding affinity to calf thymus (CT) DNA.204
Xylarisin A 239, an [11]cytochalasin derivative from Xylaria sp.
[sea fan, Annella sp., (Similan Is., Thailand)], was a weak inhibitor
of both S. aureus and MRSA. (2E,4S)-2,4-Dimethyloct-2-enoic
acid, a known synthetic compound,205 was also isolated for the
first time as a natural product.206 The benzaldehyde derivatives
240 and 241 were isolated from a mangrove endophytic fungus
[taxonomy of fungus and mangrove not given, (South China Sea
coast)]207 and the acids 242 and 243 were obtained from culture of
another unidentified mangrove endophyte (Zhanjiang sea area,
China).208 Lyngbya bouillonii (Milne Bay, Papua New Guinea)
afforded the unusual cyclic depsipeptide, alotamide A 244, with
three contiguous peptidic residues and an unsaturated heptaketide. This compound had a unique calcium influx activation
profile in murine cerebrocortical neurons.209
Grassystatins AC 245247 are linear peptides containing
a statine unit, isolated from L. confervoides (Grassy Key and Key
Largo, Florida). Grassystatins A 245 and B 246 selectively
inhibited cathepsins D and E, whereas grassystatin C 247, with
two fewer residues, was less potent but still selective for cathepsin
E.210
Chemical investigation of L. confervoides (Broward County,
Fort Lauderdale, Florida) led to the largamides AC 248250,
unusual tiglic acid-containing cyclodepsipeptides that were
moderate inhibitors of porcine pancreatic elastase activity in
vitro.211 These compounds, along with largamides DH, were
originally isolated from an Oscillatoria sp.212 but the current
isolation prompted a structural revision to replace the senecioic
acid residue originally proposed with a tiglic acid residue.213
Another collection of L. confervoides (Port Everglades Inlet,
Fort Lauderdale, Florida) yielded tiglicamides AC 251253,
also moderate inhibitors of porcine pancreatic elastase in vitro,
along with largamides AC.214
Tanikolide seco-acid 254 and tanikolide dimer 255 were isolated from a collection of L. majuscula (Tanikely Is., Madagascar). Tanikolide seco-acid 254 had been previously
synthesised as an intermediate in the synthesis of tanikolide215
but this was the first report as a natural product. Total synthesis
of the three tanikolide dimer stereoisomers permitted elucidation
of the stereochemistry of the dimer 255, a selective inhibitor of
the NAD+-dependent cytoplasmic protein, human sirtuin type 2
(SIRT2).216 The cyclodepsipeptide, hantupeptin A 256 was isolated from L. majuscula (Pulau Hantu Besar, Singapore) and was
cytotoxic to MOLT-4 and MCF-7 cells.217
Desmethoxymajusculamide C 257 was isolated from L.
majuscula (Kauviti Reef, Yanuca Is., Fiji) and was a potent and
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active in vivo in HCT-116-bearing mice with severe combined


immunodeficiency.218

From L. majuscula (True Blue Bay, Grenada) two halogenated


fatty acid amides, grenadamides B 258 and C 259, and two
depsipeptides, itralamides A 260 and B 261, were isolated. The
known depsipeptide carriebowmide219 was isolated as the sulfone
artefact, which on comparison with authentic carriebowmide led
to a minor structural revision to 262. Grenadamides B 258 and C
259 had marginal insecticidal activity against the beet armyworm
(Spodoptera exigua), while itralamide B 261 was cytotoxic to
HEK293 cells.220

selective agent against HCT-116 through disruption of cellular


microfilament networks. Interestingly, a linear version of 257,
generated through base hydrolysis, also possessed potent actin
depolymerisation characteristics and solid tumour selectivity
equivalent to 257. Desmethoxymajusculamide C 257 was also
This journal is The Royal Society of Chemistry 2011

The linear peptide desacetylmicrocolin B 263 has been isolated


from Lyngbya cf. polychroa (Hollywood, Florida) as a growth
inhibitor of HT-29 and IMR-32 cells,221 while extraction of
Lyngbya semiplena (Tumon Bay, Guam) resulted in isolation of
the cyclodepsipeptides lyngbyastatins 810 264266, inhibitors
of porcine pancreatic elastase.222
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Chemical investigation of a collection of Lyngbya sp. (Okinawa) resulted in isolation of biselyngbyaside 267, an 18membered macrolide glycoside with broad-spectrum cytotoxicity
in a human tumour cell line panel, likely by a novel mechanism as
indicated by COMPARE analyses.223

Bisebromoamide 268 was isolated from Lyngbya sp. (Okinawa), and was cytotoxic to HeLa S3 cells and a panel of human
cancer cell lines, in addition to exhibiting potent protein kinase
inhibition.224

An assemblage of Lyngbya majuscula and Phormidium gracile


(Hola Bay, Papua New Guinea) yielded hoiamide A 269, a cyclic
depsipeptide, of mixed peptidepolyketide biosynthetic origin,
which was a partial agonist of site 2 on the voltage-gated sodium
channel.225
The same Symploca sp. sample (Pillars, Key Largo, Florida)
that produced largazole226,227 was the source of symplostatin 4
270, a highly functionalised linear peptide with features from
both dolastatin 10 and 15, but with modest activity only against
212 | Nat. Prod. Rep., 2011, 28, 196268

HeLa and HT-29 cells and several orders of magnitude less


potent than either dolastatin 10 or dolastatin 15 at disrupting
cellular microtubules.228 Symplostatin 4 270 had the same planar
structure as gallinamide A, isolated from Schizothrix sp. (Piedras
Gallinas, Panama), and moderate activity against Plasmodium
falciparum, Leishmania donovani and mammalian Vero cells.229
The absolute configuration of gallinamide A was not fully
determined, and NMR spectral comparison of the two metabolites indicated that they may be different.228

Spirolides H 271 and I 272 were isolated from culture of


Alexandrium ostenfeldii (Ship Harbour, Nova Scotia) and are
structurally distinct from other spirolides in that they contain
a 5 : 6 dispiroketal ring system rather than the trispiroketal ring
system characteristic of previously isolated spirolides. Spirolide
H 271 displayed only extremely weak toxicity in a mouse
bioassay, in contrast to previously isolated spirolides.230 Analysis of ROE and geometrical constraints, the latter derived from
1
H-1H and 1H-13C coupling constants, combined with molecular
dynamics and molecular mechanics calculations led to the
assignment of the full relative configuration of 13,19-didesmethylspirolide C.231,232 The analysis also identified three major
conformations of the toxin present as an equilibrium in solution.

Carteraol E 273, a polyhydroxyl metabolite isolated from


Amphidinium carterae [seaweed washings, (southern coast of
Taiwan)], was a potent ichthyotoxin, in addition to being active
against Aspergillus niger.233 Cooliatin 274, an unusual
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dioxocyclononane, was isolated from Coolia monotis [coastal


seaweeds, (Hainan Is., China)].234

The polyether brevisin 275 was isolated from Karenia brevis


(Wilsons 58 clone) and has an unprecedented structure that
consists of two separate fused polyether ring assemblies linked
via a methylene group. Brevisin 275 inhibited the binding of
brevetoxin-3 to voltage-sensitive sodium channels in rat brain
synaptosomes.235

Culture of Prorocentrum belizeanum (source not given) led to


the polyunsaturated, polyhydroxylated macrocycle, belizeanolide 276, and the open-chain form, belizeanolic acid 277. Both
compounds had significant antiproliferative activities against
several human solid tumour cell lines.236
Formosalides A 278 and B 279, 17-membered ring macrolides,
were isolated from culture of Prorocentrum sp. [seaweed washings, (South Bay, Taiwan)].237
A Symbiodinium sp. [flatworm, Amphiscolops sp., (Sesoko Is.,
Okinawa)] was the source of the long carbon-chain compounds,
symbiospirol AC 280282, with symbiospirol A 280 inhibitory
against L-phosphatidylserine-induced PKC activation.238
Aspergillides A and B are cytotoxic macrolides isolated from
Aspergillus ostianus.239 Enantioselective synthesis of the
proposed structure of aspergillide A indicated that revision of
that structure to that proposed for aspergillide B 283 was
necessary. The structure of aspergillide A as originally published
was incorrect, but the actual structure was unclear.240 Subsequently, the original researchers, assisted by X-ray analysis,
published a structural revision of both compounds to establish
aspergillide A as 284 and aspergillide B as 283.241 Total synthesis
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of aspergillide C, also from Aspergillus ostianus,239 was accomplished from a commercially available chiral glycidol derivative.242 The structure of neomarinone, a furanonaphthoquinone,
isolated from a marine filamentous bacterium243 was revised after
a biosynthetic study and NMR analysis.244 The total synthesis of
neomarinone (utilising a regioselective DielsAlder reaction) has
now been achieved, and established the absolute configuration as
285.245

Total synthesis of both isomers of the bisanthraquinone antibiotic BE-43472B, originally isolated from Streptomyces sp.
found in a cyanobacterium associated with the ascidian Ecteinascidia turbinata,246 was achieved via a cascade sequence initiated by an intermolecular DielsAlder reaction, and defined the
absolute configuration of the natural product as 286.247,248

Aquastatin A, previously isolated from Fusarium aquaeductuum,249 has now been isolated from the marine environment

214 | Nat. Prod. Rep., 2011, 28, 196268

(Cosmospora sp. [sediment, (Gejae Is., S. Korea)] and the absolute configuration determined (287).250 Malyngamides O and P
were originally isolated from the sea hare Stylocheilus longicauda,251 whilst malyngamides Q and R were isolated from the
cyanobacterium Lyngbya majuscula.252 All four metabolites have
now been synthesised via a flexible and convergent route, which
established the configurations of malyngamides Q and R as 288
and 289 respectively.253,254
Ypaomide was isolated as a herbivore-feeding deterrent from
the cyanobacterium Lyngbya majuscula.255 An enantioselective
synthesis of the (R)-enantiomer established that the natural
product was the (S)-enantiomer 290.256

Total synthesis of amphidinolactone A from the cultured


dinoflagellate Amphidinium sp. [flatworm, Amphiscolops sp.],257
was accomplished via a ring-closing metathesis reaction and
established the absolute configuration (291).258 A further
member of the series, amphidinolide V,259 was also synthesised
utilising a ring-closing alkyne metathesis, again establishing the
absolute configuration 292.260,261

Amphidinolide Q, isolated from the same Amphidinium


sp.,262,263 has been stereoselectively synthesised by a scheme that
combined Julia coupling, Myers alkylation, and Yamaguchi lactonisation.264 Caboxamycin, a known intermediate in the
synthesis of benzoxazole carboxamides,265 has been described as
a natural product for the first time following isolation from
Streptomyces sp. [deep-sea sediment, (Canary Basin, Atlantic
Ocean)]. Caboxamycin was an inhibitor of Gram-positive
bacteria and a moderate inhibitor of several cancer cell lines.266
Methyl 3-(3-oxocyclopent-1-enyl)propionate was isolated for the
first time as a natural product from Trichoderma atroviride [sediment, roots of Ceriops tagal, (South China Sea)]267 but had
previously been synthesised.268 A number of bile acid derivatives
were isolated from culture of Psychrobacter sp. [Stelletta sp.,
(Geoje Is., S. Korea)]. Of these, 3-dimethoxy-12a-hydroxycholanic acid was a new derivative, but assumed to be an artefact.
3-Dimethoxy-7-ketocholanic acid,269 while known, was isolated
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from a natural source for the first time. It too may also be an
artefact. Finally, 12a-hydroxy-3-ketocholanic acid270 and 12ahydroxy-3,7-diketocholanic acid,271 while known, were isolated
from a marine source for the first time.272 Culture of Halobacillus
salinus [sea grass, (South Kingstown, Rhode Is., USA)] produced
N-(20 -phenylethyl)isobutyramide,273 a known inhibitor of
quorum sensing-regulated behaviour in Gram-negative bacteria,
but isolated from a marine source for the first time.274 Known
fungal metabolites pyripyropene A, B and D275 were isolated from
Aspergillus sp. [sediment, (Gokasyo Gulf, Japan] as selective
antiproliferative substances against human umbilical vein endothelial cells (HUVECs). Pyripyropenes B and D were isolated
from the marine environment for the first time.276 Marinoquinoline A, a pyrroloquinoline from the marine gliding bacterium
Rapidithrix thailandica,277 exhibited strong inhibition of acetylcholinesterase. Two related pyrrole derivatives, 3-(20 -aminophenyl)pyrrole278 and 2,2-dimethylpyrrolo-1,2-dihydroquinoline,
were isolated from two other strains of R. thailandica, but the
quinoline was proposed as an artefact of the pyrrole, which was
isolated from a natural source for the first time.279 Culture of an
unidentified fungal strain isolated from a sea salt pan in Australia
resulted in the first marine-based isolation of 3-O-methylfunicone,280 a selective inhibitor of mammalian Y-family DNA
polymerases (pols) and growth suppressor of HCT-116 and HeLa
cells.281 N-Methyl-2-indolecarboxamide, a known synthetic
compound,282 was isolated from a natural source for the first time
as a metabolite of Cladosporium cladosporiodes [Cliona sp., (Los
Molles, Chile)]283 while 2,20 -dithiobis-benzothiazole, a known
plant metabolite,284 was isolated from the marine environment for
the first time from an unidentified endophytic fungus [mangrove,
(South China Sea)].285 The known terrestrial fungal siderophore
fusigen286 was isolated from the marine environment for the first
time from the fungus Aureobasidium pullulans [sea saltern,
(Yellow Sea, China)] as a growth inhibitor of Vibrio anguillarum
and V. parahaemolyticus.287 Sporolide B, a halogenated macrolide
from the actinomycete Salinispora tropica,288 was synthesised by
a convergent strategy featuring a ruthenium-catalysed [2 + 2 + 2]
cycloaddition reaction,289 while synthesis of bacillamide 3, originally isolated from Bacillus endophyticus [hypersaline microbial
mat, (Bahamas)],290 was accomplished from D-alanine.291 The
total synthesis of emericellamide B, a metabolite of the fungus
Emericella sp. produced during co-culture with the actinomycete
Salinispora arenicola,292 was achieved by a flexible, convergent
strategy.293 Gymnastatins F294 and Q,295 metabolites of the fungus
Gymnascella dankaliensis (Halichondria japonica), were synthesised via a biomimetic route from the corresponding spirodienone derivatives.296 The first297 of several298300 total
syntheses of brevisamide, a cyclic ether alkaloid from the dinoflagellate Karenia brevis,301 was achieved in 21 linear steps from
cis-but-2-ene-1,4-diol.297 A series of synthetic studies established
the configurations of various fragments of symbiodinolide,
a polyol macrolide from the symbiotic marine dinoflagellate
Symbiodinium sp.302 For example, a stereoselective synthesis of the
C-23C-34 bis-epoxide fragment of symbiodinolide and related
diastereomers
led
to
configurational
revision
to
(26S,27R,28R,29S,30R,32S),303 while synthesis of the C-14C-23
fragment established the configurations (17S,18R,21R).304
Synthesis of the C-33C-42 fragment established the configurations (36S,40S),305,306 and also the absolute configuration of the
This journal is The Royal Society of Chemistry 2011

C-10 C-250 fragment.307 Xyloketal B, one of a series of ketals


isolated from the mangrove fungus Xylaria sp.,308 protected
HUVECs against oxidised low density lipoprotein (LDL)induced cell injury,309 in addition to giving protection of rat
pheochromocytoma (PC12) cells in an in vitro oxygen glucose
deprivation (OGD) model of ischemic stroke.310 Beneficial effects
appear to be associated with these free radical-scavenging and
antioxidant properties.310 The known diketopiperazines
Sch54796311 and Sch54794311 were isolated from Penicillium sp.
[mangrove species not given, (South China Sea)] as inhibitors of
laryngeal cancer hep2 and hepatoma hepG2 cell lines.312
Fermentation of an unidentified marine fungus (source not given)
yielded a number of known metabolites of which decarboxydihydrocitrinone313 was inhibitory to MRSA.314 Mycalamide A,
a metabolite of the sponge Mycale hentscheli,315 and pederin,
isolated from Paederus spp. rove beetles,316 are structurally similar
polyketides. Three methyltransferases, part of a previously isolated set of genes from a bacterial endosymbiont, were incubated
with mycalamide A to produce a non-natural hybrid compound,
18-O-methylmycalamide A which possessed increased cytotoxicity, providing evidence that invertebrates can obtain defensive
metabolites from bacterial symbionts.317 This work was carried
out on the 10 mg scale, with the identity of the product derived
from the 1H NMR spectrum acquired in a capillary NMR probe.
Most of the enzymes responsible for spiroketal formation and
epoxidation in griseorhodin A318 biosynthesis were identified
through generation of 14 gene-deletion variants of the biosynthetic gene cluster isolated from a Streptomyces sp. (Aplidium
lenticulum).319 Streptomyces maritimus produces the enterocin
family of polyketides.320 Priming the enterocin biosynthetic
enzymes with unnatural substrates led to ex vivo multienzyme
syntheses of 24 unnatural 5-deoxyenterocin and wailupemycin F
and G analogues, of which 18 were new.321 Feeding experiments
using 13C-labelled sodium acetate precursors revealed that all 25
carbon atoms in the skeleton of aspergiolide A, a metabolite of the
filamentous fungus Aspergillus glaucus,322,323 were derived from
labelled acetate.324 The effects of biosynthetic pathway specific
inhibitors and precursors on aspergiolide A production were
investigated in a novel strategy involving simultaneous feeding of
both, which resulted in greatly enhanced aspergiolide A production.325 Biosynthetic studies of curacin A, a metabolite of mixed
polyketide-peptideorigin from the cyanobacterium Lyngbya
majuscula,326 revealed an unprecedented decarboxylative chain
termination mechanism involving a module containing adjacent
sulfotransferase (ST) and thioesterase (TE) catalytic domains.327
Studies on the biotransformation of bromosesquiterpenes in the
fungi, Rhinocladiella atrovirens328 and Rhinocladiella sp. from
the Okinawan brown alga Stypopodium zonale,329 indicated that
the former fungus converted aplysistatin into 5a-hydroxyaplysistatin, 5a-hydroxyisoaplysistatin and 9b-hydroxyaplysistatin, whilst the latter fungus, transformed aplysistatin,
palisadin A and 12-hydroxypalisadin B to 3,4-dihydroaplysistatin
and 9,10-dehydrobromopalisadin A.330

Green algae

The chemistry of the abundant and relatively easy to collect


members of the phylum Chlorophyta continues to be underrepresented. In 2009 there were only 30 papers published, with
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the majority being descriptive, or dealing with polysaccharide


chemistry. A bioactivity-directed analysis of Ulva fasciata
(Aabu-Qir, Mediterranean coast, Egypt) characterised three new
unsaturated fatty acids 293295 and a further ten known nonpolar metabolites identified by GCMS.331

The ubiquitous monoterpene loliolide332 was found in thirteen


red, brown and green algae from the Black Sea. This was the first
report of loliolide from green algae.333 Debromocymopolone,
296 was isolated from Cymopolia barbata (Fairy Hill Beach,
Jamaica), and is the first non-halogenated cymopol isolated.334

A significant find was the discovery of two new cyclic depsipeptides from Bryopsis pennata (Kahala Bay, Ohau, Hawaii).
These were 5-OHKF 297 and norKA 298, and join the other
seventeen congeners of the kahalide family that have to date been
isolated from B. pennata or molluscs of the genus Elysia. Interestingly, 5-OHKF 297 showed no antitumour properties, in
keeping with the importance of the aliphatic group in the known
compounds KF 299 and isoKF 300.335 Six known sterols were
identified from Chaetomorpha basiretorsa.336 In each case this
was the first discovery of these compounds from that genus.
The biological roles of two well-known Caulerpa metabolites
have been examined. Both natural (+)-caulerpenyne and the
synthetic enantiomer inhibited microtubule formation, with the
() enantiomer having a lower IC50 for inhibition of tubulin
polymerisation.337 In this recent study, ()-caulerpenyne was
demonstrated to bind slowly to tubulin in a non-covalent and
poorly reversed fashion, but not at the colchicine, Taxol or

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Vinca-alkaloid binding sites.338 Caulerpin, a Caulerpa sp.


pigment,339 but also found in Chondria sp.340 has been established
as an inhibitor of mitochondrial respiration at complex 1, suppressing hypoxic activation of HIF-1, an important target in
anticancer drug discovery.341 The first syntheses of two Caulerpa
taxifolia metabolites, taxifolione and taxifolial D, were reported
and the surprising (Z) configuration for taxifolial D
confirmed.342 Metabolomics technology was successfully applied
in a proof-of-principle study to assess environmental risk factors
using the unicellular Scendesmus vacuolatus as test organism.343

Brown algae

The majority of the new metabolites from brown algae each year
were terpenoid, or part terpenoid in origin. In 2009 well over half
of the 60 papers published were descriptive in nature, or dealt
with sulfated polysaccharide (fucoidan) chemistry. Eicosapentaenoic acid, isolated for the first time from Zonaria tournefortii (Tipaza, Algeria), was proposed as the biosynthetic
precursor for the co-occuring acylphloroglucinols and chromone
derivatives.344 The diacylglycerol 301 was reported from Zonaria
diesingiana (unspecified location, South China Sea),345 while
ishigoside 302 was isolated from Ishige okamurae (Busan, S.
Korea). The free-radical-scavenging activity of ishigoside 302
was evaluated using an ESR technique.346

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A bioactivity study of the fibrinolytic properties of Sargassum


fulvellum (East Sea, China), selected from 700 samples, identified
the bioactives as the known diacylglycerols MOGG and POGG.
This was the first isolation of these compounds from a marine
source.347 In another large survey, 342 species of marine alga
were screened against the bacterium Propionibacterium acnes,
and the bacteriostatic compound sargafuran 303 was isolated
from Sargassum macrocarpum (Japan). Sargafuran, a novel
compound suggested to be of geranylgeraniol/shikimate origin,
had low cytotoxicity and could be the basis of a new skin care
treatment to prevent or improve acne.348

Two brominated selinane sesquiterpenoids 304 and 305 and


five known sesquiterpenes were isolated from Dictyopteris
divaricata (Yantan, Shandong Province, China).349 This same
alga was also the source of the cadinane sesquiterpenes 306 and
307, and six other known cadinanes.350,351

Hydroperoxides have rarely been found in algae: two examples,


dictyohydroperoxide, 308 and hydroperoxyacetoxycrenulide 309,
were isolated from Dictyota dichotoma (Troitsa Bay, Sea of
Japan, Russia) along with 15 other known diterpenoid and
steroidal secondary metabolites.352

In a study of a Mediterranean Dictyota sp. (Le Brusc Lagoon,


France), a new xenicane 310 and three new dolabellanes 311313
were characterised in addition to seven previously reported
diterpenoids. A study was carried out on the antifouling properties of the more abundant of this series against Pseudoalteromonas sp.353 Despite differences in the magnitude of the optical
rotation, the absolute configuration of the xenicane diterpenoid
()-4-hydroxydictyolactone 314 from Dictyota ciliolata354 has
been determined from synthesis via an enantiocontrolled route
utilising the B-alkyl Suzuki reaction to incorporate the (E)alkene in a direct ring closure.355
The inhibitory activity of two known dolastanes from Dictyota
cericornis (Baia da Ribeira, Brazil) against mammalian Na+K+ATPase was evaluated.356 Seven new members of the rare 2,6This journal is The Royal Society of Chemistry 2011

cyclo-xenicane skeleton, 315321, were obtained from Dilophus


fasciola (Cap Zebib, Tunisia) and D. spiralis (Elafonissos Island,
Greece). Xenicane 315 was isolated from D. spiralis and 316321
from D. fasciola. In addition, seven previously reported metabolites were isolated.357

A brassinosteroid-related compound 322 was isolated from


Cystoseira myrica (Fayed, Egypt) in an investigation centered on
the cytotoxic activity of the extract against two human cancer cell
lines.358 Cytoseira compressa (Tunisia) was the origin of the sterol
saoussazine 323, discovered along with fucosterol,359 while from
Sargassum fusiforme (location not specified) six known sterols
and two known glycolipids were reported. For both glycolipids
this was the first isolation from this genus.360

Three new meroditerpenoids, 324326, along with four known


metabolites, were isolated from Sargassum fallax (Port Phillip
Bay, Australia).361
Eight known compounds and two new meroditerpenoids 327
and 328, which included a halogenated derivative 328, from
Stypopodium flabelliforme (Hanga Roa, Easter Island) were
characterised as the derived peracetates. This is the first occurrence of a halogenated Stypopodium metabolite.362
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of 329.368 In addition to having radical-scavenging activity, 329


was a potent inhibitor of a-glucosidase and a-amylase, with
possible potential as a functional food or nutraceutical for diabetes.369
The antioxidant and anti-inflammatory properties of phlorotannins from Ecklonia stolonifera and E. cava have been
investigated.370,371 In further studies, the suppressive effects of
eckstolonol372 and phlorofucofuroeckol A373 (E. stolonifera) on
Fc3RI expression (antiallergenic) was examined,374 and the role
of two phlorotannins from E. cava in inducing apoptosis in
MCF-7 cells evaluated.375

Red algae

The number of new compounds reported from red algae in 2009


has recovered from a marked reduction in 2008 to levels more
typical for the previous years. Six weakly cytotoxic 1-glyceryl
ethers, ceratodictyols AF 330335, were obtained from a mixed
assemblage of the red alga Ceratodictyon spongiosum and the
sponge Haliclona cymaeformis (Kurosaki, Japan). These 1-alkylglyceryl ethers were unusual in having oxygenation in the alkyl
chain.376

The absolute configuration of ()-stypotriol was determined,


as the triacetate, by application of vibrational CD spectroscopy.
This was the first direct assignment of configuration as this
previously had relied on the several syntheses, from chiral
substrates, of ()-stypoldione, the air-oxidation product. With
300 electrons, this is to date the largest natural product
successfully studied by VCD.363 A reassignment of configuration
has been reported for the meroditerpenoids from a Korean
Sargassum siliquastrum,364 and requires revision of the C-130
configuration for six of the structures.365 The alga Leathsia nana
was a rich source of bromophenols,366 and six compounds have
now been evaluated in vitro against eight human tumour cell lines
and protein tyrosine kinase (PTK) (with over-expression of ckit). All compounds were modestly cytotoxic and three were
strong inhibitors of PTK.367 Use of an antioxidant assay led to
the isolation of the phlorotannin diphlorethohydroxycarmalol
329 from the abundant Japanese alga Ishige okamurae. ESR
techniques were used to establish the radical-scavenging activity

A collection of Laurencia grandulifera (Loutraki Bay, Crete)


yielded five lauthisan derivatives 336340, some of which showed
modest antistaphylococcal activity.377 In a separate report, five
C15 tetrahydrofuran-containing acetogenins 341345 and
a linear biosynthetic precursor 346 were described from this same
collection of L. grandulifera.378

Neurymenolides A 347 and B 348 are two a-pyrone macrolides


isolated from Neurymenia fraxinifolia (Taveuni, Fiji). Neurymenolide A, which consists of quickly interchanging atropisomers, had moderate potency against MRSA, VREF strains
and a range of tumour cell lines. Neurymenolide B showed only
modest MRSA activity.379 Plocamium cornutum (Kalk Bay, S.
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(Hainan coastline, China) provided three sesquiterpenes 358360


and the norsesquiterpene 361.384

Africa) was the source of five antiplasmodial (to a chloroquinesensitive strain of Plasmodium falciparum) halogenated monoterpenes, of which the two new ones 349 and 350 were the least
active.380

The new sesquiterpene 362, along with fifteen other known


sesquiterpenes, was obtained from L. similis (Sanya Bay,
China).385 The brominated diterpene neorogioltriol 363, which
has analgesic properties, was obtained from L. glandulifera
(Kefalonia Is., Greece),386 while Sphaerococcus coronopifolius
(Corfu Is., Greece) yielded the neodolabellane diterpenes
sphaerollane I 364 and II 365, together with the sphaeroane
diterpene 366.387

Several rearranged chamigrane sesquiterpenes were obtained


from Laurencia composita (Nanji Is., China). Two, 2-bromospironippol 351 and laurencomposidiene 352, were new.
Confusingly, 351 was named as laurencomposene elsewhere in
this paper.381 It was suggested that the occurrence of rearranged
chamigranes in L. composita but not in L. okamurai could
provide a useful chemotaxonomic marker to distinguish these
two similar species, but this argument is not supported by the
report, by the same authors, of laurenokamurin 353 in L. okamurai (Weihai coastline, China).382

L. saitoi (Shandong Province, China) yielded the halogenated


chamigranes 354 and 355, together with 356 and 357 as an
inseparable 1 : 1 mixture.383 Another collection of L. saitoi
This journal is The Royal Society of Chemistry 2011

The metamorphosis-enhancing macrodiolide, luminaolide


367, was isolated from the crustose coralline alga Hydrolithon
reinboldii. Based on the similarity of this compound to others
previously reported from cyanobacteria, it was speculated that
luminaolide may be produced by epiphytic bacteria on the
surface of the H. reinboldii.388
In a study on the phytochemical profiling of Laurencia filiformis
(St. Pauls Beach, Australia) by conventional and HPLC-NMR
methods, new aromatic sesquiterpenes cycloisoallolaurinterol 368
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and isoallolaurinterol 369 were isolated.389 It was suggested that


these may have been formed as artefacts from allolaurinterol.
Several other known compounds were also characterised in this
study, including filiformin,390 for which the first X-ray diffraction
study was secured.

bromoindole alkaloids 373 and 374 were isolated from Laurencia


similis (Sanya Bay, China).394
A further study on Callophycus serratus (Yanuca, Fiji) has
yielded an additional suite of unusual antimalarial diterpenebenzoate macrolides, bromophycolides JQ 375382. These
bromophycolides also showed a range of moderate to strong
antimicrobial and anticancer activities.395

The weakly antimicrobial bromoether 370 was isolated from


Symphyocladia latiuscula (Qingdao, China).391 The bromophenol
371 was obtained from Polysiphonia urceolata (Yantai, China)
and characterised by spectroscopic techniques and DFT theoretical analysis.392

By using a novel stacked HSQC mask dereplication strategy


on partially purified mixtures from algal extracts, a new nitrogenous bromophenol, colensolide A 372, was identified from
Osmundaria colensoi (Northland, New Zealand).393 Two

The biologically active halophenol 2,20 ,3,30 -tetrabromo4,40 ,5,50 -tetrahydroxydiphenylmethane, originally from Rhodomela larix,396 was synthesised along with a series of related
halogenated bis(hydroxyphenyl)methanes in a study of antimicrobial activities.397 The syntheses of four analogues of the
oxylipin agardhilactone (Agardhiella subulata)398 has resulted in
a revision of the absolute configuration of this compound.399
Radioactive 82Br was used in a study of the biosynthesis of laurencin, laureatin and other brominated metabolites in some
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Laurencia species.400 Reactive desorption electrospray mass


spectrometry (DESI-MS) is a promising technique and permits
MS experiments under ambient environmental condition. In this
example, three bromophycolides, implicated as antimicrobial
defense compounds, were directly detected on the surface of
Callophycus serratus.401 This technique is applicable to a wide
range of surface types, not just red alga.

7 Sponges
The number of new compounds reported from sponges in 2009
(287) is similar to that in each of the previous few years. The alkyl
amino alcohol halaminol A (Haliclona sp.)402 induced rapid
larval settling in ascidians but prevented their subsequent
metamorphosis. For the larvae of other phyla, halaminol A
inhibited settlement, and was toxic.403 Iotrochotamides I 383 and
II 384 were isolated from Iotrochota purpurea (Pulau, Indonesia).404 A Haliclona species (Jeddah, Saudi Arabia) yielded
a series of cytotoxic sphingolipids, 385390.405

Largo, Florida).409 Rhizochalina incrustata (Madagascar) yielded


the bipolar sphingolipid isorhizochalin 408.410

The absolute configuration of leucettamol A 391 (Leucetta


microrhaphis)406 was determined by a deconvolution of superimposed exciton coupled circular dichroism spectra of a hydrogenated N,N0 ,O,O0 -benzoyl derivative.407 Leucettamol A was
previously claimed as a racemate due to its undetectable optical
rotation.406

A Haliclona (Reniera) species (Ulleung Is., S. Korea) contained a series of glucocerebrosides, renierosides C1C3, C5C14
392404.408

Amphiceramides A 405 and B 406 and the related N-acetylglucoside 407 were obtained from Amphimedon compressa (Key
This journal is The Royal Society of Chemistry 2011

The taurine derivative 2-palmitamidoethane sulfonic acid


409 was isolated from Haliclona sp. (Hainan Is., China).411 A
series of glycerol ethers 348353 isolated from the sponge/red
alga assemblage Haliclona cymaeformis/Ceratodictyon spongiosum is described in the previous section of this review. Theonella swinhoei (Sulawesi, Indonesia) yielded aurantoic acid
410.412

The bromine-containing motualevic acids AF 411416 and


(4E)-(R)-antazirine 417, isolated from Siliquariaspongia sp.
(Motualevu Reef, Fiji), were active against MRSA.413
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The carteriosulfonic acids AC 418420, isolated from Carteriospongia sp. (San Miguel Is., Philippines), were inhibitors of
the kinase GSK-3b.414
A series of long-chain-substituted pyrroles, mycalenitriles 414
421431 and mycalazals 1420 432438, inhibited HIF-1 activation in human breast tumour cells.415
Jaspine B (Jaspis sp.)416 inhibited sphingomyelin synthase in
human melanoma cells, thereby increasing ceramide levels and
thus triggering apoptosis which accounts for the compounds
reported cytotoxicity.417 The cytotoxic acetylenes 439 and 440
and the unusual dihydrothiopyranone 441 were obtained from
Reniochalina sp. (Chuuk, Micronesia).418 A weakly cytotoxic and
weakly antimicrobial thiophene 442 was obtained from the
calcareous sponge Paragrantia cf. waguensis (Okinawa).419
A Petrosia species, collected by dredging (150 m, Kurose Hole,
Hachijo Is., S. Korea), contained the cytotoxic neopetroformynes AD 443446.420
Diacarnus bismarckensis (Sanaroa, Papua New Guinea) yielded ent-()-muqubilone 447 and (+)-muqubilone B 448, active
against Trypanosoma brucei (African sleeping sickness).421

The absolute configuration of muqubilone (Diacarnus erythraeanus)422 was assigned by the establishment of absolute
configuration of 447. The aromatic peroxides 449452 and
compounds 453 and 454 were isolated from Plakortis sp. (Orote
Peninsula, Guam); 449452 were weakly active against S.
aureus.423

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Plakinic acids I 455 and J 456 were obtained from Plakortis


halichondrioides, and absolute configurations determined from
CD curves by degradation and liposomal ordering of naphthamide derivatives.424 Melophlins P, Q and R (Melophlus sp.)425
have been synthesised,426 as have plakortethers F427 and G427
(Plakortis simplex).428

The antimalarial gracilioethers AC 457459 were isolated


from Agelas gracilis (Oshima-Shinsone, Japan). Compounds 458
and 459 were generally cytotoxic, while 458 was also active
against Leishmania major.429 (+)-Spiculoic acid (Plakortis angulospiculatus)430 has been synthesised.431 Total synthesis432 has
established the absolute configuration of tedanalactam 460
(Tedania ignis),433 and syntheses of bengazoles C and E (Jaspis
sp.)434 have been reported.435

proline residues. Rolloamide B, while showing some evidence of


a minor conformer, was determined to be predominantly the allcis conformer.440 Prosuberites laughlini (Aguadilla, Puerto Rico)
contained a cytotoxic tryptophan-containing cyclic peptide,
euryjanicin A 468. While an X-ray analysis revealed all-cis
conformers, there was NMR spectral evidence of another form in
solution.441

A total synthesis of theopederin B (Theonella sp.)436 has also


been achieved using an SmI2-promoted Reformatsky reaction.437
A Callyspongia species (Hainan Is., China) yielded callyspongidipeptide A 461 and the related dipeptide 462.438

Citronamides A 463 and B 464, isolated from Citronia astra


(Day Reef, Queensland, Australia), were moderately active
against S. cerevisiae (bakers yeast).439
The proline-rich cyclic peptides rolloamide A 465, 466 and B
467 were obtained from Eurypon laughlini (Rollo Head, Dominica). Rolloamide A was cytotoxic and existed as two
conformers with independent sets of NMR resonances attributable to cis 465 and trans 466 conformers around one of the
This journal is The Royal Society of Chemistry 2011

In a subsequent report by the same research group, the


isolation of euryjanicins BD 469471 from the same sponge
was reported.442 The reported structure of euryjanicin C 470 is
identical to the previously reported rolloamide B 467 in all
respects except for a trans instead of a cis rotamer of one proline
residue. Since the NMR data were recorded in different
solvents, it is unclear whether the two reports represent the same
structures.
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The cyclic peptides perthamide C 472 and D 473, isolated from


Theonella swinhoei (Vangunu Is., Solomon Is.), were antiinflammatory in a mouse oedema model, while lacking cytotoxicity.443

An enantiomeric synthesis of stylisin 1 (Stylissa caribica)444 has


been reported.445 Halicylindramide A (Halichondria cylindrata)446 was synthesised enantiospecifically.447 Siliquariaspongia
mirabilis (Sulawesi, Indonesia) has yielded two classes of polyketide-containing cyclic peptides, celebeside AC 474476 and
theopapuamides BD 477479. Celebeside A 474 inibited HIV-1
proliferation, while the theopapuamides were cytotoxic.448
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Nine new homophymines, BE 480483 and A1E1 484488,


isolated from Homophymia sp. (New Caledonia), were potently
antiproliferative to HL60 cells.449

Total syntheses of the tryptophan-containing peptides kapakahine B and F (Cribrochalina olemda)450,451 have been
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reported.452 Jaspis splendans (Vanuatu) contained the cytotoxic


jaspamides MP 489492.453

The nitrogenous bismacrolide tausalarin C 493, isolated from


Fascaplysinopsis sp. (Salary Bay, Madagascar), was anti-proliferative towards leukaemia cells.454 In the same study, the relative
This journal is The Royal Society of Chemistry 2011

configuration of salarin A 494 (Fascaplysinopsis sp.)455 was


determined by X-ray analysis. Pateamine (Mycale sp.)456 has
been shown to bind to eIFAIII and inhibit nonsense-mediated
decay of messenger RNA.457 The structure of hemi-phorboxazole
A 495, isolated from Phorbas sp. (Australia), was established
from a total sample of 16.5 mg using a cryogenic capillary NMR
probe.458 A total synthesis has also been reported establishing
absolute configuration. Unlike other members of the series, it
was not bioactive.459 From the same specimen of Phorbas sp.
(Australia) the chlorocyclopropyl-bearing macrolide muironolide A 496 was isolated. The configuration of the chlorocyclopropyl appendage was determined via degradation and
synthesis.460

Zampanolide, originally isolated from Fasciospongia rimosa


(Cape Zampa, Okinawa),461 has recently been re-isolated from
Cacospongia mycofijiensis (Eua, Tonga) and found to be
a potent microtubule-stabilising agent.462 The synthesis of its
natural (+) enantiomer has also been reported.463 Neolaulimalide
(Fasciospongia rimosa)464 and isolaulimalide (Hyattella sp.),465
congeners of the potent microtubule-stabilising laulimalide, have
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been synthesised. Neolaulimalide was shown to have potent


microtubule stabilising activity.466 Four potently cytotoxic halichondrin B congeners, B-1140 497, B-1092 498, B-1020 499 and
B-1076 500, were obtained from a large collection of Lissodendoryx sp. (Kaikoura, New Zealand), with their structures
being determined on the nanomole scale using a capillary NMR
probe.467

The potent a-glucosidase inhibitors, schulzeine AC (Penares


schulzei),472 have been synthesised, revising the C-200 configuration of schulzeine A 509 from (S) to (R).473 A biomimetic
synthesis of pyrinadine A (Cribrochalina sp.)474 confirmed the
assigned trans azoxy functionality and suggested a hydroxylamine origin.475 The alkylpyridinium salts pachychaline D 510,
didehydropachychaline A 511, norpachychaline A 512 and
dinorpachychaline A 513 were isolated from Callyspongia sp.
(Martinique). A biogenic scheme linking these and other alkylpyridine metabolites to the presumed precursor norspermidines
was also presented.476

The Arctic sponge Haliclona viscosa (Kongsfjorden, Svalbard)


was the source of haliclamines E 514 and F 515; structures were
established by MS analysis and synthesis of model
compounds.477 The weakly cytotoxic cyclic alkylpyridinium salts
516 and 517 were obtained from Haliclona sp. (Pacific Coast,
The diphenyl ethers 501 and 502 were isolated from Dysidea
(Lamellodysidea) herbacea (Vim Levu, Fiji) while 503 and 504
were isolated from Dysidea granulosa (Milne Bay, Papua New
Guinea). All were mild inhibitors of Bcl-2 activity.468

The modified amino acids axiphenylalaninium 505 and


axityrosinium 506 were obtained from Axinella polypoides
(Marseille, France).469 A mildly cytotoxic cyclic diamine, 1,5diazacyclohenicosane 507, was isolated from Mycale sp. (Lamu
Is., Kenya).470 Plakoridine C 508, obtained from Plakortis sp.
(Manzamo, Okinawa), was a racemic and also a 1 : 1 cis/trans
mixture of isomers.471
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Guatemala).478 Njaoaminiums AC 518520 were isolated from


Reniera sp. (Pemba Is., Tanzania); 519 showed weak cytotoxicity.479
The ecological role of alkylpyridinium alkaloids was investigated for Amphimedon chloros, from which halitoxin (Haliclona
sp.)480 and amphitoxins (Amphimedon compressa)481 were isolated. These compounds were selectively toxic towards saltwater
bacteria, but not those associated with A. chloros.482 The absolute
configurations of the tetracyclic haliclonacyclamines A 521 and
B 522 (Haliclona sp.)483 were determined by X-ray analysis.
Interestingly, they have opposite signs of rotation but are of the
same enantiomeric series.484 The related 22-hydroxyhaliclonacyclamine B 523, isolated from Haliclona sp. (Flores Is.,
Indonesia), together with haliclonacyclamines A and B, were

This journal is The Royal Society of Chemistry 2011

active against TB-causing Mycobacterium smegmatis and M.


bovis under both aerobic and hypoxic conditions.485
The moderately cytotoxic and antibacterial haliclonin A 524
was isolated from Haliclona sp. (Jeju Is., S. Korea).486
The cytotoxic manzamine-type alkaloids zamamidine A 525
and B 526 were isolated from Amphimedon sp. (Seragaki, Okinawa).487 In a subsequent report the same group has described
zamamidine C 527 with antitrypanosomal and antimalarial
activity along with the related 3,4-dihydro-6-hydroxy-10,11epoxymanzamine A 528 and 3,4-dihydromanzamine J N-oxide
529.488,489

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An Axinella species (Sanya, Hainan Is., China) yielded the


indole alkaloid 530.490 A Hyrtios species (Chuuk, Micronesia)
contained 1-carboxy-6-hydroxy-3,4-dihydro-b-carboline 531.491
Aaptanone 532 was isolated from Aaptos aaptos (Cu Lao Re Is.,
Vietnam).492 An inibitor of EGF-induced malignant transformation of murine epidermal cells, 3-N-morpholinyl-9-demethyl(oxy)aaptamine 533, was isolated from Aaptos sp. (Vang
Fong Bay, Vietnam).493
Tsitsikammamine A (Latrunculiidae)494 has been synthesised.495 The discorhabdin congeners (+)-dihydrodiscorhabdin A 534, (+)-debromodiscorhabdin A 535 and
(+)-discorhabdin X 536 were isolated from Higginsia sp. (South
Australia).496 The structure of dihydrodiscorhabdin A was
subsequently revised from 534 to the epimeric 537.497,498
(+)-Dihydrodiscorhabdin L 538 was isolated from Spongosorites sp. (South Australia).496 Latrunculia (Biannulata) wellingtonesis (Wellington, New Zealand) yielded the cytotoxic

(6R,8S)-1-thiomethyldiscorhabdin G*/I 539 and both enantiomers of 16a,17a-dehydrodiscorhabdin W 540.497


A synthesis of neolamellarin A (Dendrilla nigra)499 has been
reported.500 A series of bromopyrroles, acanthamides AD 541
544, and the related 545 and 546, were isolated from Acanthostylotella sp. (Bali, Indonesia).501
(Z)-Axinohydantoin and (Z)-debromoaxinohydantoin (Stylotella aurantium)502 have been synthesised.503 Syntheses of
ceratamines A and B (Pseudoceratina sp.)504 have been reported.505 The antibacterial and antifungal nagelamides Q 547 and R
548 were isolated from Agelas sp. collected from Seragaki and
Unten-Port, Okinawa, respectively.506

()-Dibromophakellin (Phakellia flabellata)507 has been


obtained from Acanthella costata (Sykes Reef, Great Barrier

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Reef) and was an a2B adrenoceptor agonist.508 The enantiomer,


(+)-dibromophakellin, has been synthesised.509 Nagelamides O
549 and P 550 and mukanadins E 551 and F 552 were isolated
from several collections of Agelas sp. (Okinawa). Nagelamide O
549 was weakly antibacterial, nagelamide P 550 was isolated as
a racemate, and mukanadin F 552 was weakly antifungal.510

Benzosceptrin A 553 and nagelamides S 554 and T 555 were


isolated from Agelas cf. mauritiana (Guadalcanal, Solomon Is.)
while benzosceptrin B 556 was isolated from Phakellia sp. (New
Caledonia).511 Benzosceptrin C 557 was isolated from Agelas sp.
(Unten-Port, Okinawa).512 The reported structure of nagelamide
D (Agelas sp.)513 has been synthesised, but the spectral data differ
slightly from the natural compound.514

Merobatzelladines A 558 and B 559, with activity against


bacteria, Plasmodium falciparum (malaria) and Trypanosoma
brucei brucei (sleeping sickness), were isolated from Monanchora
sp. (Amami-Oshima, Japan).515,516 Norbatzelladine A 560,
dinorbatzelladine A 561, dinordehydrobatzelladine A 562,
dinorbatzelladine B 563 and dihomodehydrobatzelladine C 564
were isolated from Monanchora arbuscula (Martinique), while
norbatzelladine L 565 and clathriadic acid 566 were isolated from
Clathria calla (Guadeloupe). All compounds were cytotoxic.517
The bromotyrosine alkaloid content of Aplysina sp. (Croatia)
was different between deep-water and shallow-water individual
specimens. These differences were stable to transplantation and
artificial culture.518 Clavatadines CE 567569, from Suberea
clavata (Queensland, Australia), weakly inhibited serine protease
factor XIa.519
Molokaiamine (Pseudoceratina arabica)520 has been synthesised.521 In an independent study the related alkaloid molokaiamide, originally isolated along with molokaiamine,520 has
also been synthesised.522 The cytotoxic bromotyrosine dimerThis journal is The Royal Society of Chemistry 2011

derived alkaloid, JBIR-44 570, was obtained from Psammaplysilla purpurea (Kinwan Bay, Okinawa).523 The non-selective
pyruvate
phosphate
dikinase
(PPDK)
inhibitor
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19-hydroxyaraplysillin-I N20-sulfamate 571 was isolated from


Ianthella flabelliformis (Shelburne Bay, Queensland, Australia).524

The structure of psammaplin I (Pseudoceratina purpurea)525


has been revised from a sulfone to a sulfinate ester 572. This
paper also reported the isolation of the related compounds 573
575 from P. purpurea.526

Tyrokeradine A 576 and the antimicrobial tyrokeradine B 577


were isolated from a Verongid sponge (Kerama Is., Okinawa).527
The cytotoxic aphrocallistin 578 was isolated from the

hexactinellid Aphrocallistes beatrix collected by submersible


(Fort Pierce, Florida). It was also synthesised and found to cause
G1 arrest.528
The merosesquiterpenoid dysideamine 579, isolated from
Dysidea sp. (Indonesia), was neuroprotective against iodoacetic
acid-induced cell death in mouse neurons.529 Dysidea villosa
(Hainan Is., China) yielded the human protein tyrosine phosphatase 1B (hPTB1B) inhibitor 21-dehydroxybolinaquinone
580.530

Puupehanol 581 was isolated from Hyrtios sp. (Papua New


Guinea); the absolute configuration was determined from
extensive calculated ECD spectra. Interestingly, a simple application of the octant rule predicted the wrong configuration.531 20epi-Hydroxyhaterumadienone 582 and 15-oxo-puupehenoic acid
583 were isolated from Hyrtios sp. (Pocklington Reef, Papua
New Guinea).532

A racemic synthesis of smenochromene D and subsequent


chiral separation has shown that ()-smenochromene D 584
(Smenospongia sp.)533 and (+)-likonide B 585 (Hyatella sp.)534 are
enantiomers, and suggests that neither of the original isolations
were enantiopure.535 Dysidine (Dysidea sp.)536 promoted glucose
uptake in cells, probably by inhibition of protein tyrosine
phosphatase PTP1B.537 A Spheciospongia species (Sanya, Hainan
Is., China) yielded the norterpenoids spheciospongone A 586 and
B 587.538

Dysifragilisins A 588 and B 589 were isolated from Dysidea


fragilis (Sanya, Hainan Is., China), but the authors of the report
suggest that they were artefacts of acetone extraction, as they
were not detected in a chloroform extraction of the sponge.539
Aignopsanoic acid 590, the methyl ester 591, and isoaignopsanoic acid 592 were isolated from Cacospongia mycofijiensis (Kimbe Bay, Papua New Guinea); 590 and 591 were
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moderately active against Trypanosoma brucei.540 The


nitrogenous isopyrodysinoic acid 593, 13-hydroxyisopyrodysinoic acid 594 and pyrodysinoic acid B 595 were obtained
from Dysidea robusta (Bahia, Brazil).541

Nakijiquinones E 596 and F 597 were obtained from Spongia


sp. (Unten-Port, Okinawa).542

The cytotoxic norditerpenoids, gracilins JL 598600, were


isolated from Spongionella sp. (West Angaur, Philippines), of
which 600 was active against protein tyrosine kinase EGF-R.543
A synthesis of xestenone 601 (Xestospongia vanilla)544 established the relative configuration at C-12 and the absolute
configuration,545 while synthesis of phorbasin C 602 (Phorbas
sp.)546 established the relative configuration at C-11 as well as the
absolute configuration.547
The moderately cytotoxic 10-epi-kalihinol X 603 was obtained
from Acanthella sp. (Yalong Bay, Hainan Is., China).548 Tedania
ignis (Sweeting Cay, Grand Bahama Is.) yielded tedanol 604,
which was anti-inflammatory in mice.549

Dysidea cf. arenaria (Okinawa) contained a series of spongian


diterpenoids 605611, of which 606, 610 and 611 were cytotoxic.550

Isospongiatriol 612, and 3-nor-spongianones A 613 and B 614


were isolated from Spongia sp. (Fiji).551

A series of weakly antiplasmodial amphilectane diterpenoids


615619 were isolated from Cymbastela hooperi (Kelso Reef,
Queensland, Australia).552 A Ciocalapata species (Koh-Tao,
Thailand) yielded 8-isocyanoamphilecta-11(20),15-diene 620.553
The enantiomer of agelasine F (Agelas nakamurai)554 has been
synthesised, confirming the absolute configuration of the natural
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Palinurin (Ircinia variabilis)558 has been synthesised.559 The


unusual spirosesterterpenoids alotaketal A 629 and B 630 were
isolated from Hamigera sp. (Milne Bay, Papua New Guinea) and
found to activate the cAMP cell signalling pathway.560
The closely related, moderately cytotoxic phorbaketals AC
631633 were isolated from Phorbas sp. (Gageo Is, S. Korea).561
An enantioselective synthesis of luffalactone 634 (Luffariella
variabilis)562 established the absolute configuration.563

enantiomer.555 The norsesterterpenoids irciformonin EK 621


627 were isolated from Ircinia formosana (Taiwan), of which
irciformonin I was found to inhibit peripheral blood mononuclear cell proliferation. In the same study irciformonin A
(Ircinia formosana)556 was re-isolated and the structure revised to
628.557

Coscinolactams A 635 and B 636, isolated from Coscinoderma


mathewsi (Vangunu Is., Solomon Is.), were moderately antiinflammatory and inhibited PGE2 and NO production in cells.564

A synthesis of petrosaspongiolide R 637 (Petrosaspongia


nigra)565 from ()-sclareol established the absolute configuration.566 Antifouling activity has been reported567 for the sesterterpenoids (7E,12E,20Z)-variabilin (Sarcotragus sp.),568
cavernosolide (Fasciospongia cavernosa)569 and lintenolide A
(Cacospongia cf. linteiformis).570 The scalarane-type sesterterpenoids 638641 were isolated from Carteriospongia foliascens
(Sulawesi, Indonesia); compounds 638, 640 and 641 inhibited
human Ras-converting enzyme (hRCE protease).571

The rearranged sesterterpenoid similan A 642 and the related


scalaranoids 643645 were obtained from Hyrtios gumminae
(Similan Is. Andaman Sea, Thailand); 645 was weakly cytotoxic.572
Phyllofolactone L 646, cytotoxic phyllofenone D 647 and
phyllofenone E 648 were isolated from Phyllospongia foliascens
(Yongxing Is., China).573
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Heteronemin acetate,574 12-O-deacetyl-19-deoxyscalarin575


and sesterstatin-5576 (Hyrtios erecta), were synthesised from
heteronemin isolated from Hyrtios sp. (American Samoa).577
Scalarolide (Spongia idia)578 has been synthesised.579 The antimicrobial sesterterpenoid alkaloids 19-oxofasciospongine A 649,
fasciospongine C 650 and 25-hydroxyhalisulfate 9 651 were isolated from Fasciospongia sp. (Palau).580
A synthesis of the nor-steroid nakiterpiosin 652 (Terpios
hoshinota)581 revised the relative configurations at C-6, C-20 and
C-25 and established the absolute configuration.582 The steroid
653 originated from Axinella sp. (Sanya, Hainan Is., China).490

Theonella swinhoei (Sulawesi, Indonesia) was the source of


dehydroconicasterol 654.412 Aragusteroketal B 655 was isolated
from Ianthella sp. (Namyet Is., Vietnam).583

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A Psammoclema species (Nelson Bay, NSW, Australia) contained the antiproliferative steroids 656659.584 Petrosterol-3,6dione 660 and 5,6a-epoxy-petrosterol 661, isolated from
Ianthella sp. (Namyet Is., Vietnam), were cytotoxic and caused
apoptosis.585
The norselic acids AE 662666, isolated from Crella sp.
(Norsel Point, Palmer Station, Antarctica), were weakly antimicrobial and antifeedants to mesograzers.586

Haplosamate A (Xestospongia sp.)587,588 was shown to be


a cannabinoid receptor binder by saturation transfer doubledifference NMR spectroscopy.589 Geodisterol-3-O-sulfite 667
and 29-demethylgeodisterol-O-sulfite 668, isolated from Topsentia sp. (Chuuk, Micronesia), reversed efflux pump-mediated
fluconazole resistance in the yeasts S. cerevisiae and C. albicans
but had no antimicrobial activity.590 Ptilosteroids AC 669671
and ptilosaponosides A 672 and B 673 were isolated from Ptilocaulis spiculifer (New Georgia Is., Solomon Is.).591

The steroidal glycosides pandaroside AD 674677 and the


methyl esters of pandarosides A 678, C 679 and D 680 were
obtained from Pandaros acanthifolium (Martinique).592
The bis-steroids fibrosterol sulfate AC 681683, were isolated
from Lissodendoryx (Acanthodoryx) fibrosa (Coron Is., Philippines); 682 and 683 were found to inhibit protein kinase C z
(PKCz).593
Phorbas amaranthus (Key Largo, Florida) yielded the amaroxocanes A 684 and B 685, of which 685 was also found to deter
feeding by bluehead wrasse.594
The sipholane-type triterpenoids 686, sipholenone E 687,
sipholenols JM 688691, siphonellinols D 692 and E 693 and
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siphonellinol hydroperoxide 694 were obtained from Callyspongia (Siphonochalina) siphonella (Hurghada, Red Sea,
Egypt). In the same report the structure of sipholenol I 695 (S.
siphonella)595 was revised.596

stony coral (Eastern Coast, Red Sea) was approximately three


times greater in summer than winter, an observation in keeping
with the suggested putative ecological roles as UV-protectants.597
Oxylipin 696, isolated by bioassay-directed fractionation
(Sinularia numerosa, Kagoshima Prefecture, Japan), inhibited
tube-formation in a human endothelial cell line model of
angiogenesis.598

Cerebrosides sarcoehrenosides A 697 and B 698 were isolated


from Sarcophyton ehrenbergi (Dongsha Is., Taiwan) and reduced
expression of pro-inflammatory inducible nitric oxide synthetase
(iNOS) in a murine macrophage cell line.599

A South China Sea collection of S. infundibuliforme yielded the


glycosylglycerols sarcoglycosides AC 699701, which were
mildly toxic to Artemia salina.600

8 Cnidarians
There was a pronounced decline in the number of new metabolites reported from cnidarians compared with previous years. The
total content of mycosporine-like amino acids in six species of
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The meroterpenoid sarcophytonone 702, isolated from Sarcophyton crassocaule (Lingshui Bay, Hainan Province, South
China Sea), also exhibited mild toxicity to Artemia salina.601
Asymmetric synthesis of the originally proposed structure of
the cytotoxic hydroid (Gymnangium regae) pentapeptide gymnangiamide602 requires that the configuration of the terminal aguanidino-serine residue be reassigned from L- to D- as shown
(703).603

A highly strained cyclo-1,3-carbazole structure 704 (antipathine A) was deduced for a metabolite isolated from the black
coral Antipathes dichotoma (Sanya, Hainan Province, South
China Sea).604 Cycloaplysinopsin C 705, a dimeric alkaloid isolated from the hard coral Tubastraea sp. (Hanish Is., Yemen),
had micromolar antimalarial activity towards both chloroquinesensitive and chloroquine-resistant strains of Plasmodium falciparum.605

In addition to a number of xeniaphyllane diterpenes (see later),


the norhumulene gibberosin N 706 was isolated from
a Taiwanese collection of Sinularia gibberosa.606 Nor-sesquiterpene 707 was isolated from Nephthea sp. (Sibuan Is., Sabah,
Malaysia).607 (+)-(7S,10R)-10,11-Epoxycurcuphenol 708, previously reported as a semi-synthetic derivative of (+)-curcuphenol,608 has been isolated as a natural product from Echinomuricea
sp. (Taiwan).609

The sec-germacrane sesquiterpene 709 was isolated from


Nephthea chabroli (Siaoliouciou Is., Taiwan), whilst a specimen
of N. erecta (Green Is., Taiwan) yielded the unusual antibacterial
mercaptan-containing sesquiterpene erectathiol 710.610 In separate publications, sesquiterpenes 711 and 712611 and the mildly
cytotoxic eudesmanoid and nor-eudesmanoid sesquiterpenes
713715612 were also reported from extracts of N. erecta collected
at the same Taiwanese location.
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In addition to a range of known diterpene and steroidal


metabolites, two examples of the rare bulgarane-skeleton
sesquiterpenes, alcyonicene 716 and deacetoxy-alcyonicene 717,
were isolated from the soft coral Alcyonium antarcticum (Terra
Nova Bay, Antarctica).613 A deep-sea dredging campaign in the
Western Weddell Sea, Antarctica, afforded specimens of A.
grandis from which new congeners 718726 of the alcyopterosin
family of sesquiterpenes were purified.614 Methanolysis of lactone
726 provided an alcohol, enabling assignment of absolute
configuration.

Nor-sesquiterpene nephthediol 727 and bicyclic sesquiterpene


nephthetetraol 728 were isolated from Nephthea sp. (Bay of
Sanya, Hainan Is., South China Sea).615

Taenialactams A 729 and B 730 and taenialactone A 731, close


analogues of terrestrial sesquiterpenes, were reported from
extracts of Cespitularia taeniata (Green Is., Taiwan).616 Two
separate publications have reported the isolation of caryophyllane skeleton sesquiterpenes; rumphellolide H 732, previously noted from the plant Cyperus longus617 (and as
a semisynthetic product from caryophyllene oxide),618 and rumphellolide I 733, from Rumphella antipathies (Southern coast,
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Taiwan).619,620 The carbon skeleton of capillosanol 734 (Sinularia


capillosa, Dongsha Atoll, Taiwan) is novel while the highly
condensed, nor-sesquiterpene structure of the mildly cytotoxic
chabranol 735, (Nephthea chabroli, Siaoliouciou Is., Taiwan), is
likely derived from oxidative demethylation of a sesquiterpene
precursor.621

Methyl 5-[(10 E,50 E)-20 ,60 -dimethylocta-10 ,50 ,70 -trienyl]furan-3carboxylate (Sinularia capillosa)622 induces apoptosis via a caspase-dependent pathway in the THP-1 leukaemia cell line.623
Extensive in vitro and in vivo evaluations of the soft coral
sesquiterpene metabolite D9(12)-capnellene-8b,10a-diol624 and
a monoacetate derivative established inhibition of interferon-gstimulated expression of inducible nitric oxide synthase and
cyclooxygenase-2, and so represent lead compounds in the
development of new treatments of neuroinflammatory effects.625
An examination of the sesquiterpene chemistry of over 100
individuals of five of the six known species of soft corals of the
genus Plexaurella has determined that there was no correlation
between species and chemistry, nor was there any correlation

This journal is The Royal Society of Chemistry 2011

between location or depth and chemistry.626 The structure of an


unusual antineuroinflammatory C18 terpene metabolite nanolobatolide 736, isolated from a Taiwanese collection of Sinularia
nanolobata, was established.627 The proposed biogenesis of 736
was by DielsAlder addition of acrylic acid to a guaianesesquiterpene. Further investigation of extracts of Pseudopterogorgia elisabethae (San Andres Is., Colombia) yielded four
diterpenes, elisabethadienol 737, 7-hydroxyerogorgiaenone 738,
7,14-erogorgiaenediol 739, and elisabethin A acetate 740, a norditerpene sandresolide C 741, a bisnorditerpene elisabethin G
742 and the C15-rearranged metabolite elisabethin H 743. Elisabethin H was proposed to be a pentanorditerpene, and was
modestly antimycobacterial with antineuroinflammatory activities. Sandresolide C 741 was mildly antimalarial with no significant cytotoxicity.628
The pseudopterosins, diterpene glycoside metabolites of P.
elisabethae, undergo oxidation and proton transfer, eliciting an
intramolecular ring closure that leads to a dramatic change in
conformation, which is possibly relevant to the well known antiinflammatory activity of this class.629 Nine examples of eunicellin-diterpenes, simplexins AI 744752, were isolated from
Klyxum simplex (Dongsha Atoll, Taiwan).630 Simplexin E
reduced iNOS and COX-2 protein expression in macrophage
cells, while simplexins A and D only had an effect on iNOS
protein expression. Cultivated specimens of K. simplex afforded
the closely related diterpenes klysimplexins AH 753760.631

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Modest cytotoxicity was observed for klysimplexins B and H.


The structure of the unusual rearranged diterpene aberrarone
761 (Pseudopterogorgia elisabethae, San Andres Is., Colombia)
was secured.632 Moderate antimalarial activity was observed for
the metabolite. Investigation of hexane extracts of the same
organism collected from the same locale led to the characterisation of elisapterosin F 762.633
As with previous years, a large number of cembrane diterpenes
have been reported from cnidarians. The monoexpoxide-containing cembranes knightol 763, knightol acetate 764 and
knightal 765 were isolated from the sea whip Eunicea knighti
(Santa Marta Bay, Colombian Caribbean).634 A library of
natural product and semi-synthetic cembranes exhibited activity
against a range of marine Gram-positive and -negative bacteria,
while 763 and 765 were active in an anti-quorum-sensing
bioassay.

configuration of durumolide J 775 was the same as that reported


for lobophytolide D (Lobophytum sp.),644 though major differences in specific rotation and NMR chemical shifts were
observed, especially at C-1 and C-13, suggesting that they are in
fact diastereomers.

A collection of Sinularia sp. (Lingshui Bay, Hainan Province,


South China Sea) afforded diepoxycembrene A 766,635 while
a collection of Lobophytum sp. from the same locale yielded
11,12-epoxy-sarcophytoxide 767.636

g-Lactone-containing sarcophyolide A 768 was isolated from


South China Sea specimens of Sarcophyton sp.637 and the related
diterpene 769 and ring-opened analogue secosarcophinolide 770
were also isolated from South China Sea collections of Sarcophyton glaucum.638 The absolute configuration of 769, which is
enantiomeric to a cembrane previously reported as a semisynthetic derivative of sarcophine639 and as a natural product
from S. trocheliophorum,640 was confirmed by semi-synthesis
from ent-sarcophine,641,642 and an X-ray analysis.
trans-Fused a-methylene-g-lactone-containing durumolides
FL 771777 were isolated from an extract of Lobophytum durum
(Dongsha Is., South China Sea).643 The structure and relative
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The structures of crassocolides GM 778784 (Sarcophyton


crassocaule, Kenting, Taiwan) contain either an epoxide group
or were derived from epoxide precursors.645 Mild cytotoxicity
was observed for most of the metabolites.
The erroneous cis-fused a-methylene g-lactone structural
depiction of lobomichaolide 785 (Lobophytum michaelae),646
originally established by an X-ray analysis, has recently been
corrected to the trans-fused lactone shown.647 The 1,4-diketocontaining cembranoid leptogorgolide 786 and three related
furanocembranolides, leptodiol 787, leptodiol-7-acetate 788 and
8-epi-lopholide 789, were isolated from Leptogorgia sp. (Jicarita,
Panama).648 The authors discussed the concept of genus-specific
oxidation at C-18 as a taxonomic marker for octocorals, and in
particular suggested that furanocembranolides such as 787789
may be biosynthetic precursors to 1,4-diketo-cembranoids such
as 786.

and the precursor cembrane pseudopterolide.653 Both bisditerpenoids were prepared by bubbling NH3 through a solution
of pseudopterolide. Mild cytotoxicity was exhibited by 793.

The structures and relative configurations of the sevenmembered lactone-containing diterpenes sinulaparvalide A 794
and B 795 (Sinularia parva, Lingshui Bay, Hainan Province,
South China Sea) were established.654 The structurally-related
lactones flexibilisolide A 796 and ring-opened analogue flexibilisin A 797 were isolated from cultivated specimens of Sinularia flexibilis, while flexibilisolide B 798 and flexibilisin B 799
were isolated from wild specimens of the same species (Southern
Pintung, Taiwan).655 Base-catalysed hydrolysis of the cometabolites 11-epi-sinulariolide acetate656 and sinulariolide657
yielded 797 and 799 respectively.

Lobocrasol 790 (Lobophytum crassum, Dongsha Is., Taiwan)649 and corallolides A 791 and B 792 (Pseudopterogorgia
bipinnata, Providencia Is., Colombia)650 embody unusual carbon
skeletons and exhibit mild biological activities.

A Sweeting Cay (Bahamas) collection of P. acerosa gave the


asymmetric dialkylamine bis(pseudopterane)amine 793,651 as
well as the known symmetric analogue bis(gorgiacerol)amine652
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A Kenting (Taiwan) collection of S. flexibilis yielded a diverse


array of cembranoids, including new examples named flexilarins
AJ 800809.658 The structure and relative configuration of
flexilarin A 800 was determined, while acetylation of flexilarin I
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808 yielded a product identical with querciformolide C.659


Moderate cytotoxicity was observed for a number of the flexilarins, especially 803, towards the Hep2 cell line.

The structurally-related 3-lactones sinuladiterpene AF 810


815 were reported from a Green Is. (Taiwan) collection of S.
flexibilis.660
The unusual a-methylene cis-fused d-lactone hemiketals durumhemiketalolide AC 816818, isolated from Lobophytum
durum (Dongsha Is., Taiwan), were potent inhibitors of iNOS
expression in stimulated macrophage cells.661 The structures and
absolute configurations of new congeners of the decaryiol family
of bicyclic diterpenes, decaryiol BD 819821 (Lobophytum sp.,
Siladen Is., North Sulawesi, Indonesia) have been reported.662 A
small library of decaryiol analogues was prepared, and O-methyl
decaryiol identified with moderate levels of cytotoxicity towards
a glioma cell line.

Norverticillanes cespihypotin W 822 and X 823, and verticillane diterpenes cespihypotin Y 824 and Z 825 and cespihypotone 826 were sourced from Cespitularia hypotentaculata
(Green Is., Taiwan).663

Eight new biscembranes have been reported from two studies


of soft corals of the genus Sarcophyton. Seven mildly cytotoxic
examples, bisglaucumlides EK 827833, were isolated from S.
glaucum (Amami Oshima, Kagoshima Prefecture, Japan).664 The
absolute configurations of 827 and 829833 were determined by
comparison of ECD data with those reported for congeners
bisglaucumlides A and C.665 The eighth biscembrane, methyl
tortuoate D 834, was isolated from S. tortuosum as a result of
ESIMS screening, which indicated the presence of a molecular
ion peak that did not correspond to any previously reported
metabolites from this soft coral.666 A full account of the total
synthesis of related biscembrane methyl sarcophytoate667 has
been published.668
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Investigation of the chemistry of the hybrid soft coral Sinularia


maxima  S. polydactyla yielded five new terpenoids bearing
a cembraneafricanane skeleton.669 The absolute configuration
of (7E)-polymaxenolide 835 was established by a combination of
Cu Ka radiation X-ray analysis and theoretical calculations of
ECD spectra, while analysis of NOE and ECD data established
the absolute configurations of the remaining new metabolites,
(7E)-5-epipolymaxenolide 836 and polymaxenolides AC 837
839.669
A new norditerpene bearing a xenicane skeleton, isoacalycixeniolide A 840, was isolated from Acanthogorgia turgida
(Grandi Is., Goa, India).670 Absolute configuration was assigned
(ORD), with the same absolute configuration also being ascribed
to co-metabolites acalycigorgin E671 and acalycixeniolides B672
and G.673,674 In addition to a number of known briaranes, the
new example juncin ZII 841 was reported from Junceella juncea
(Sanya, Hainan Province, China).675 Potent antifouling activity
(Balanus amphitrite) was observed for both 841 and the structurally related briarane gemmacolide B.676

A Tai-Tong County (Taiwan) collection of Junceella juncea


yielded juncenolides HK 842845.677

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Juncenolide H is a C-2,C-9 diastereomer of gemmacolide C.676


Chlorinated briaranes fragilide EG 846848 were isolated from
Southern Taiwan collections of Junceella fragilis.678,679 The
structure and absolute configuration of fragilide F, isolated from
a male specimen of the gorgonian, was established. Fragilide G
was isolated from a female specimen of the same organism. The
study also questioned the assignments of 1H NMR and MS data,
but not the structure, for the previously reported briarane junceellonoid D.680
Briaexcavatins UZ 849854 were isolated from cultivated
specimens of Briareum excavatum (Taiwan).681,682 Briaexcavatin
Y 853 contains an unusual 8,9-epoxide group; the same paper682
also summarised the 13C NMR chemical shifts associated with borientated 11,12-epoxide-containing briarane diterpenes.

While excavatoids A 855 and B 856 were isolated from cultivated specimens of B. excavatum, wild-type specimens of the
same organism (Southern Taiwan) yielded the 5,6-epoxy-briaranes excavatoids C 857 and D 858.683
The structures and relative configurations of excavatoid A 855,
and cultivated gorgonian known co-metabolite briaexcavatin
I,684 were established. Excavatoid C 857 is unusual in that it bears
a 3-lactone ring. A second publication reported the characterisation of excavatoids E 859 and F 860 from the same samples of
cultivated B. excavatum.685 Both metabolites were modest
inhibitors of elastase release from human neutrophils.
The xenicane diterpenes asterolaurin AF 861866 (Asterospicularia laurae, southern coast, Taiwan) generally inhibited
elastase release and superoxide production by human neutrophils.686
In addition to the norhumulene metabolite presented earlier,
xeniaphyllanes gibberosin OS 867871 and sinugibberoside
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F 872 were isolated from Sinularia gibberosa (northeastern coast,


Taiwan).606 Two related congeners, 9,11-secosterols 873876,
were isolated from Eunicella cavolini (Lichadonissia Is.,
Greece).687 Moderate levels of in vitro cytotoxicity were observed
towards human prostate and breast adenocarcinoma cell lines.
Of four new steroids (ximaosteroids AD 877880) isolated
from Scleronephthya sp. (Ximao Is., Hainan Province, China),
ximaosteroid A was unusual in that it contained a fused tetrahydrofuran moiety.688 Chabrosterol 881, a 19-norergostane
derivative, was reported from extracts of Nephthea chabroli
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887.689 Two of these sterols, 886 and 887, were also isolated from
an ascidian Trididemnum inarmatum (Achladi Bay, Maliakos
Gulf, Greece).

A number of the new and known epidioxysterols showed


differential growth inhibition of MCF-7 cells depending upon the
cell culture conditions and media used. A Tsau-Lou-Cho Is.
(Taiwan) collection of Nephthea chabroli afforded the C-19oxygenated sterols nebrosteroids IL 888891 and the 4amethylated sterol nebrosteroid M 892.690 Of the five steroids, all
but 890 reduced the levels of expression of iNOS and COX-2
proteins in stimulated murine macrophages.
(Siaoliouciou Is., Taiwan)610 and the related ergostanoids 882
884 came from N. erecta (Green Is., Taiwan).611 The absolute
configurations at C-23 in 882 and C-22 in 884 were determined
(Mosher). Both 882 and 884 reduced the expression of iNOS and
COX-2 proteins in LPS-stimulated murine macrophages.

Eunicella cavolini (Lichadonissia Is., Greece), the source of


secosterols 873876, also harboured 5a,8a-epidioxysterols 885
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A second example of a 4a-methylated sterol, 893, was reported


from Nephthea sp. (Sepanggar Is., Sabah, Malaysia).691 Ring A
dienone-containing sterol 894 and regular sterol 895 were
reported from Chromonephthea sp. (Naozhou Is., South China
Sea),692 while related dienone sterols 896 and 897 were isolated
from a North Sulawesi (Indonesia) collection of Minabea sp.693
Sterol 896 was previously reported as a microbial degradation
product of cholesterol,694 and the methyl ester derivative has
been isolated from the Antarctic soft coral Anthomastus bathyproctus.695 A (25S)-configuration was assigned to 897 after
analysis of 1H NMR shift differences observed between (S)- and
(R)-phenylglycine methylester amide analogues.
Synthesis of hippuristanol (Isis hippuris)696 has yielded a small
library of related analogues. Biological evaluation of the library
identified the importance of spiroketal stereochemistry and the
presence/absence of methyl groups.697 Further study of Palythoa
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Artificial predation of Sinularia polydactyla led to a statistically significant increase in production of 11b-acetoxypukalide699
which correlated with upregulation of gene expression.700 A
study of light dependency on the growth, budding frequency and
production of flexibilide701 by cultivated Sinularia flexibilis found
a curvilinear response, indicating that both low and high light
intensity were detrimental to growth and metabolite production.702 A comparative study of fatty acid content of soft corals
that either harbour symbionts or are symbiont-free suggests that
18:3n6, 18:4n3 and 16:2n7 acids are markers of the presence
of zooxanthellae.703 Concentrations of several fatty acids in
zooxanthellae associated with jellyfish of the genus Cassiopea
decrease with a decrease in light intensity, but the same acids
increase in concentration in host tissue.704 A Plane Is.
(Marseilles) collection of the colonial sea anemone Parazoanthus
axinellae, an epibiont on the sponge Axinella damicornis, afforded the 3,5-disubstituted hydantoins parazoanthine AE 899
903.705 Absolute configuration at C-5 of 899, and by analogy 902,

toxica obtained from the fabled tidepool on the island of Maui,


the original source of palytoxin, has now revealed the presence of
a second toxin, 42-hydroxypalytoxin 898.698 Comparative biological studies of the two toxins on skeletal muscle cells indicated
that they have remarkably similar mechanisms of action.
Preliminary data suggested the new toxin has an additional Na+dependent mechanism of action that was independent from the
palytoxin target Na+/K+ pump.

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was determined by comparison of experimental ECD spectra


with time-dependent DFT calculated spectra. Parazoanthine C
was micromolar-active in the Microtox assay.
Dimethylsulfoniopropionate (DMSP) and the volatile
decomposition product dimethylsulfide play important roles in
global sulfur cycling: DMSP has been shown to be produced by
the zooxanthellae in the symbiotic pairing of the anemone Aiptasia pallida and Symbiodinium bermudense.706 Bandaporin, 20
kDa pore-forming actinoporin-family toxin, was isolated from
the anemone Anthopleura asiatica (Banda, Tateyama, Japan).707
The toxin exhibited lethal toxicity to crayfish and was potently
haemolytic towards red blood cells, though the latter activity was
inhibited specifically by sphingomyelin. UcI, a 30 kDa poreforming cytolytic toxin, was isolated from the Northern red
anemone Urticina crassicornis.708 Model studies of haemolysis,
using lipid vesicles, established that the presence of both sphingomyelin and cholesterol facilitates toxin binding to membranes.
A further new actinoporin, fragaceatoxin C (20 kDa, Actinia
fragacea, Northern Spain), was identified by a combination of
fragment sequence, RT-PCR and cloning.709 The power of solidphase peptide synthesis and native chemical ligation has been
demonstrated with the synthesis of APETx2,710 a 42-residue
toxin originally reported from Anthopleura elegantissima.711

9 Bryozoans
Although there are still very few reports on bryozoan chemistry,
there are several more this year than has been usual in past
reviews. Chemical investigations of Flustra foliacea (Minas
Basin, Bay of Fundy, Canada) resulted in 11 new flustramines F
P 904914. The dimers flustramine O 913 and flustramine P 914
may be artefacts of isolation. The metabolites possessed
a different bromination pattern from that of previously reported
flustramines712717 and some also possessed a new hydroxylation
pattern on the aromatic ring. Flustramines F 904, I 907 and L
910 had broad-spectrum antimicrobial activity.718 Investigation
of flustramines L 910 and N 912 after several years of storage
indicated a slow interconversion. Examination of flustramine H
906 indicated that it also behaves in an analogous manner, but on
a longer timescale.718

Pterocella vesiculosa (Alderman Is., New Zealand) was the


source of a new alkaloid, 5-bromo-8-methoxy-1-methylb-carboline 915, which displayed moderate inhibition of P388
murine leukaemia cells, in addition to growth inhibition of B.
subtilis, C. albicans and T. mentagrophytes.719 Investigations of
Bugula neritina (Daya Bay, Shenzhen, China) resulted in isolation of a new ceramide 916 and cerebroside 917, in addition to
some known analogues.

A cerebroside, N-[(1S,2R)-1-[(b-D-galactopyranosyloxy)methyl]-2-hydroxyheptadecyl]hexadecanamide, was claimed as


a new natural product but has been previously isolated from
myelin;720 however, the current report is the first isolation from
the marine environment.721 A new oxygenated sterol, (22Z)3a,24z,25-trihydoxycholesta-5,22-diene 918, was isolated from
Biflustra grandicella (Huang Is., Shandong Province, China).722

Bryostatin 1723 enhanced the efficacy of cytotoxic agents


through modulation of the protein kinase C pathway, and was
active in combination with vincristine for diffuse large B-cell
lymphoma.724
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10 Molluscs
The last two years have seen a considerable decline in the number
of new metabolites reported from molluscs. Mytilin-A, an antimicrobial peptide isolated from the mussel Mytilus edulis,725
exhibited moderate levels of activity towards marine Vibrio
species, yeasts and filamentous fungi that was not modulated by
saline concentrations, suggesting a potential role in the control of
marine pathogens in aquaculture settings.726 Capillary electrophoresisESI-MS has been demonstrated as an analytical tool to
detect the lipophilic marine toxins yessotoxin and pectenotoxins
with limits of detection of 10 mg kg1 and 130 mg kg1 respectively.727 The use of solid-phase extraction as an enrichment and
clean-up procedure before LCMS/MS analysis lowers the limit
of quantification for okadaic acid, pectenotoxin 2, azaspiracid 1
and yessotoxin to 1 mg kg1.728 Two new peptides of the Dsuperfamily (aD-Ms and aD-Cp) were reported from crude
venom extract of Conus mustelinus and C. capitaneus (Olango Is.,
Sebu, Philippines).729 The 11 kDa dimeric aD-conopeptides are
potent nanomolar blockers of a7, a3b2 and a4b2 subtype
neuronal nicotinic acetylcholine receptors.729,730 Lt3a is a new Mfamily toxin purified from the venom of the worm-hunting cone
snail C. litteratus (Yalong Bay, Hainan Province, South China
Sea).731 Automated sequence analysis indicated three residues
were non-standard, with subsequent comparison with a cDNA
sequence identifying carboxyglutamate and hydroxyproline
post-translational modifications (PTMs). The peptide was found
to enhance tetrodotoxin-sensitive sodium channel currents. An
86 amino acid-containing mature peptide, named con-ikot-ikot,
purified from C. striatus (unknown location), inhibits the depolarisation of glutamate-gated ion channels, leading to neuronal
death.732 Two I-superfamily peptides, ca11a (38 residues) and
ca11b (34 residues) of unknown function, were purified from the
venom of South China Sea collections of C. caracteristicus.733 A
full-length cDNA of ca11a was generated, revealing the
precursor peptide was comprised of a 20-residue signal peptide,
a 22-residue pro-peptide and a 38-residue mature peptide. Using
a cDNA probe of the signal peptide sequence, a number of new
conotoxin peptide sequences were identified, including two Osuperfamily toxins, suggesting a close evolutionary link between
I- and O-superfamily toxins. Turritoxin pal9a, isolated from the
turrid snail Polystira albida, contains 34 residues, including 6
cysteines, the pattern of which makes it a framework IX P-conotoxin peptide.734 A Mexican Caribbean Sea collection of Conus
delessertii yielded a 28 amino acid mature peptide, de7b, that
included 6 cysteines, and exists as a mixture of different
g-carboxyglutamate
and/or
4-hydroxyproline
PTM
isomorphs.735 Mass spectrometry was used to investigate the
distribution of PTM peptides related to Vc1.1 in the venom ducts
of Conus victoriae (Broom, Western Australia): the finding of
unmodified mature peptide in venom duct tissue indicated that
some of the pre- and pro- region of the immature peptide was
cleaved prior to PTM.736 The study also noted that of 3 different
disulfide isomers prepared, only the naturally occurring isomer
exhibited nAChR activity and that some PTMs were detrimental
to mammalian receptor activity. A homo-dimeric toxin,
TxXIIIA, containing an odd number of cysteine residues in the
monomer, has been identified in venom extracts of C. textile.737
The use of synthetic oligomers to probe cDNA libraries
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generated from venom duct tissue continues to lead to identification of previously unreported conotoxins.738740 Given the
potency of binding of conotoxins to their respective biological
targets, it is of no surprise that they continue to act as highly
specific molecular probes of receptors and ion channels. A
number of studies have reported on structureactivity effects of
modified a-conotoxins with nicotinic acetylcholine receptors
(nAChRs),741743 including a-ImII binding to nAChRs on
Torpedo membranes,744 the use of fluorescent analogues,745 and
the preparation and biological evaluation of a hydrolytically
stable dicarba-bridged (as opposed to disulfide-bridged) a-ImI
analogue.746 Structurally minimised analogues of the voltagegated sodium channel-targeting m-conotoxin KIIIA have been
reported to retain biological activity,747,748 and non-peptide
mimics of analgesic u-conotoxin GVIA have been reported.749,750
A chimera of u-conotoxins CVID and MVIIC, prepared using
native chemical ligation methodology, was used to investigate the
contributions of N- and C-terminal peptide segments to observed
biological activity.751 A study of the mucus and external body parts
of a Hainan (South China Sea) collection of the pulmonate mollusc
Onchidium sp. led to the characterisation of an intriguing bis-gpyrone polypropropionate, onchidione 919.752 Onchidione acted as
a strong feeding deterrent, making treated food unpalatable to
marine shrimps.

Sesquiterpenes 920922, acetogenin 923 and diterpene 924


were purified from extracts of the digestive and hermaphroditic
glands of the sea hare Aplysia fasciata (Alfacs Bay, Spain).753

Investigation of the chemistry of the herbivorous sacoglossan


slug Aplysiopsis formosa (Azores) led to the isolation of a-pyrone
polyketides aplysiopsene AD 925928.754 The structures represent shorter side chain variants of the more usual sacoglossan
polyketide metabolites such as the placidenes.755,756
Stable isotope incorporation studies with Placida dendritica
(Gulf of Naples) demonstrated a mixed acetate/propionate
polyketide biosynthetic route to the placidenes.757 Remarkably,
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the biogenesis of placidene A required only intact C3 units, an


ability previously demonstrated only by bacteria. The biosynthetic origin of Tyrian purple in Dicathais orbita has been traced
to a number of tissue types by a combination of histochemistry
and mass spectrometry.758 An L-amino acid oxidase (escapin)
present in the ink of the sea hare Aplysia californica oxidises Llysine to yield hydrogen peroxide and a number of open-chain
and cyclic piperidine products.759 Malyngamides O and P (Stylocheilus longicauda)251 structures have been confirmed by
convergent synthesis.253 Investigation of the chemistry of the
nudibranch Chromodoris willani, found feeding on an unidentified sponge that contained manoalide760 and secomanoalide,761
yielded the deoxy analogues 929 and 930.762 Both 929 (previously
reported as a synthetic intermediate763) and 930 exhibited
moderate antimicrobial activity and were less potent inhibitors of
PLA2 than manoalide and secomanoalide.
The combined use of 1 mm and 1.7 mm NMR cryo-micropobes and MS has allowed structure elucidation on the

nanomolar scale of structures 9-O-desmethylkabiramide B 931,


33-methyltetrahydrohalichondramide 932, and sanguinamides A
933 and B 934, from the extract of a single specimen of the IndoPacific nudibranch Hexabranchus sanguineus.764 Kabiramide
B,765 isolated from the same species, had potent in vitro antifungal activity, while 932 was slightly less active and 931 the least
inhibitory.
The aeolidean nudibranch Phyllodesmium lizardensis, endemic
to Lizard Is., Great Barrier Reef, sequesters muurolene sesquiterpenes 935 and 936 from its preferred host coral Heteroxenia sp.766

Further pharmacological investigations of zalypsis


(PM00104), a synthetic human antitumour agent that is structurally related to the cytotoxic marine isoquinoline alkaloids
ecteinascidin 743 (ascidian, Ecteinascidia turbinata)767,768 and
jorumycin (nudibranch, Jorunna funebris),769 continue to identify
new targets and information regarding the mechanism of action.
The drug exhibited potent activity towards multiple myeloma via
generation of DNA double-strand breaks,770 formed DNA
adducts, was particularly potent towards a gastric cancer cell
line,771 bound DNA in a different manner to ET-743,772 and
resistance to the drug could be conferred by the over-expression
of zinc finger proteins.773 A library of new nitrile-containing
analogues of jorumycin, obtained by semi-synthesis of spongederived renieramycin M,774 has expanded the structureactivity
relationship of the ester side chain of these cytotoxic agents.775

11 Tunicates (ascidians)
With 35 new metabolites being the average reported from
ascidians since 2007, the 52 natural products presented in this
review indicates elevated productivity on the part of isolation
chemists. The simple long-chain amino alcohols clavaminols G
N 937942 were isolated as bioactive constituents of the ascidian
Clavelina phlegraea (Bay of Naples, Italy).776 Limited SAR
analysis indicated that free amino and alcohol groups were
required for cytotoxicity, while the presence of an additional
hydroxyl group or lipid unsaturation were detrimental to
activity.

Two different species of Didemnum sp. (Bahia State, Brazil)


yielded the antibacterial diketopiperazines rodriguesine A 943
and B 944 and the N-acetyl analogues 945 and 946.777
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The mildly cytotoxic didemnenone congeners 947953 were


isolated from two didemnid ascidians, Lissoclinum sp. and Diplosoma sp., collected respectively from Tarama Is. and Hateruma
Is., Okinawa.778 The metabolites were detected in extracts of
Prochloron spp. separated from the two ascidians, suggesting the
symbiont was the true producer of the polyketides.

Bicyclic acids and amides 954959, isolated from a Jeju Is. (S.
Korea) collection of an unidentified didemnid ascidian, exhibited
mild cytotoxicity towards a panel of human tumour cell lines.779
Notionally, the natural products could be derived from Diels
Alder cyclisation of long chain fatty diacids.

Didemnum rubeum (Chuuk Atoll) afforded iodotyramine


derivatives 962967.781 The occurrence of 962 as a benzoate salt
and formamide 964, examples of plant or microbial-derived
natural products, suggested that 962967 may be produced by an
algal symbiont. ABCG2 is a human transporter protein linked to
multidrug resistance where it appears to play a role, amongst
others, in modulating the oral bioavailability of drugs.

Screening for inhibitors of ABCG2 led to the isolation of


a number of known alkaloids of the botryllamide family782 as
well as the characterisation of new congeners botryllamides I 968
and J 969 and revision of the structure of botryllamide H783 970
(Botryllus tyreus, Papua New Guinea).784 Extensive mechanismof-action investigations established botryllamide G to be the
most potent and specific inhibitor of ABCG2.

Meroterpenoids rossinone A 960 and B 961 were isolated from


Antarctic specimens of Aplidium sp. and exhibited a range of
anti-inflammatory and antiproliferative biological properties.780

In what appears to be the first occurrence of proaporphine


alkaloids from a marine source, saldedines A 971 and B 972 were
isolated from an unidentified ascidian (Salary Bay, Madagascar).785 Both alkaloids exhibited modest toxicity to brine
shrimp. From a collection of Leptoclinides durus (Heron Is.,
Queensland, Australia) the indole alkaloids leptoclinidamines
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AC 973975 were isolated.786 The absolute configuration of 973


was established by synthesis.

The polysulfide dopamine-derived alkaloids lissoclibadin 814


976982 were isolated as cytotoxic metabolites from Lissoclinum
cf. badium (Manado, Indonesia).787 Lissoclibadin 14 was recently
reported from a Papua New Guinea collection of the same species
and assigned the trivial name isolissoclinotoxin B.788 The particular disulfide bonding arrangements presented in lissoclibadins 9
977 and 10 978, as opposed to other isomeric possibilities, were
selected solely on the basis that they were judged to be more
thermodynamically stable by molecular mechanics calculations.
Specimens of Eudistoma sp. (Namena Is., Fiji) yielded disulfide-containing lipopeptides eudistomide A 983 and B 984. The
structures were confirmed by synthesis.789
Bioassay (neuronal nitric oxide synthase)-directed fractionation of a Great Barrier Reef collection of Eusynstyela latericius
led to the isolation and characterisation of eusynstyelamides A
C 985987.790 The spectroscopic data observed for 985 were
essentially identical to those reported for eusynstyelamide,
previously reported from a Fijian collection of E. misakiensis,791
though the metabolites exhibited opposite specific rotations. It
was concluded that the originally proposed structure of eusynstyelamide was in error and is better represented as the antipode
of 985.

The potently cytotoxic (A2780, IC50 0.34 mM) lipopeptide 39oxobistramide K 988 was isolated from Trididemnum cyclops
(Madagascar).792 The similarity of CD spectra with co-occurring
bistramide A suggested the skeletal configuration shown.
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and B 990.807 The absolute configuration of 989 was determined


(CD).
A deep-sea (Okinawa Trough, Japan) collection of the scarletcoloured stalked crinoid Proisocrinus ruberrimus yielded the
brominated anthraquinone pigments proisocrinin AF 991
996.808 The ECD spectra of 991 and 992 were equal and opposite
to those observed for 994 and 995, implying an enantiomeric
stereochemical relationship between the pairs of metabolites.
In addition to a number of known 5a,8a-epidioxysterols, two
new examples, 886 and 887, noted previously in the Cnidarian
section of this review, were isolated from the ascidian Trididemnum inarmatum (Achladi Bay, Maliakos Gulf, Greece).689
Bioassay screening led to the isolation of two antimicrobial
peptides, halocyntin (26 aa residues) and papillosin (34 aa) from
haemocytes of the solitary ascidian Halocynthia papillosa.793
Botryllazine B (Botryllus leachi)794 and analogues are mixed-type
inhibitors of recombinant human aldose reductase.795 An
improved and more efficient microwave-assisted aldol condensation reaction was used to synthesise polyandrocarpamines A
and B,796 with the former compound subsequently shown to
exhibit mild cytotoxicity towards the SF268 human tumour cell
line.797 The structures of eudistomins Y1-Y6 (Eudistoma sp.)798
have been confirmed by synthesis.799 Asymmetric synthesis of the
reported structure of eudistomidin B (Eudistoma sp.)800 indicates
the structure of the natural product requires revision.801 Racemic
syntheses of aplicyanins A, B and E (Aplidium cyaneum)802 and
a library of analogues have been reported; biological evaluation
against a panel of human tumour cell lines indicated the
importance of bromine substitution and the presence of an acetyl
group for activity.803 The structurecytotoxicity relationship of
a number of natural and unnatural lamellarin alkaloids towards
human tumour cell lines has been investigated.804 Site-directed
mutagenesis and metal-ion affinity chromatography has been
used to investigate the binding affinity of two sites of the
Vanabin2 vanadium-binding protein of Ascidia sydneiensis
samea.805 Pyura chilensis, a solitary ascidian eaten raw by coastal
populations of Chile and Peru, has been shown to contain
domoic acid, and so must now be considered a vector for
Amnesic Shellfish Poisoning.806

The structurally-related anthraquinones rhodoptilometrin809


and 3-propyl-1,6,8-trihydroxy-9,10-anthraquinone810 were reisolated from the Australian crinoid Colobometra perspinosa
(Family Is., Great Barrier Reef), and were modestly cytotoxic
towards a panel of human tumour cell lines.811 1H and 13C NMR
data observed for rhodoptilometrin were at variance with those
data previously reported. The study also reported the first
occurrences of 2-[(phenylacetyl)amino]ethanesulfonic acid and
g-hydroxybutyric acid from a marine source. Whilst galactocerebrosides have usually been reported from starfish, in
what appears to be the first report of such a metabolite from a sea
cucumber, 997 was isolated from Bohadscia argus (Zanpamisaki,
Okinawa).812 The starfish Linckia laevigata (Okinawa) yielded
a number of ganglioside natural products, from which LLG-1
998 was identified.813

12 Echinoderms
The number of new metabolites reported annually from echinoderms has remained relatively constant over the 20022008
period. Bioassay-directed (P388) fractionation of extracts of the
inter-tidal ophiuroid Ophiocoma scolopendrina gave the mildly
cytotoxic tetrameric phenylpropanoids ophiodilactones A 989

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Sterol sulfates lysaketotriol 999 and lysaketodiol 1000, isolated


from the hollow tube feet (ambulakrums) of the starfish Lysastrosoma anthosticta (Sea of Japan), were found to increase
reactive oxygen species formation by mouse macrophages.814
Evasterioside C 1001 is a 24-norsterol isolated from Evasterias
retifera (Sea of Japan).815 Given the occurrence of 24-norsterols
in phytoplankton, a food chain link source of the metabolite was
proposed. The same paper also reported the related glycosides
evasteriosides D 1002 and E 1003 from E. echinosoma (Gulf of
Shelichov, Sea of Okhotsk).
Of the five steroidal monoglycosides recently reported from
Hippasteria kurilensis (deep-sea dredging, Kuril Is., Sea of
Okhotsk), kurilensosides EG 10041006 are unusual due to the
lack of a 6-hydroxyl group.
Kurilensoside H 1007 contained a 4,5-epoxy functionality, and
1008 was the 15-sulfate analogue of co-metabolite echinastero-

This journal is The Royal Society of Chemistry 2011

side C.816 The authors also reported on the analysis of the


hydroxylation patterns of over 500 oxidised sterols from starfish
species. They proposed a dominant sequence of oxidation
processes starting at C-3 and progressing in turn from C-6, then
C-15 to C-8 that could be used to explain the substitution
patterns observed. Such a sequence highlights the unusual
finding of 10041006, which as noted earlier, lack a 6-hydroxyl
group. More regular 6-hydroxy-steroidal glycosides kurilensosides I 1009 and J 1010 were subsequently reported from the
same collection of H. kurilensis.817
The 4-O-methyl-D-GalNAc-containing glycoside anthenoside
A 1011 (Anthenea chinensis, Sanya Bay, South China Sea) was
mildly cytotoxic towards a panel of three human tumour cell
lines and also promoted tubulin polymerisation.818 The same
tubulin bioassay was used to direct the isolation of novaeguinosides AD 10121015 from the starfish Culcita novaeguineae

Nat. Prod. Rep., 2011, 28, 196268 | 251

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cytotoxicity in this series. The importance of the 24-sulfate


group for the observed tubulin polymerisation promoting
activities of these compounds was highlighted, with the finding
that 24-desulfated analogues 1016 and 1017 (isolated from the

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(Sanya Bay, South China Sea).819 By comparing structures with


other (inactive) saponins, the authors noted that the presence of
D9(11)-3b,6a-dioxysteroids bearing a sulfate group at C-3 and an
oligosaccharide at C-6 was a common structural motif for

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same organism) were inactive in the assay and less potent


cytotoxins.820
A monosulfated analogue 1018 (Actinopyga lecanora, Hainan
Is., South China Sea) of the well-known sea cucumber metabolite
holothurin B821 was unfortunately assigned a trivial name (lecanoroside A).822 Lecanoroside B 1019 was also isolated from the
extract. Bioactive triterpene glycosides 1020 and 1021 (Holothuria scabra, South China Sea) were assigned the trivial names
scabrasides A and B,823,824 which unfortunately was a duplication
of the name for a secoiridoid isolated from the rhizomes and
roots of the terrestrial plant Gentiana scabra var. buergeri.825
Holothuria (Microthele) axiloga, also collected from Hainan
Is., South China Sea, yielded arguside F 1022, impatienside B
1023 and pervicoside D 1024, of which only impatienside B
exhibited broad-spectrum antifungal activity.826 The closely
related sulfated triterpenes achlioniceosides A1A3 10251027
were reported from Achlionice violaecuspidata ( Rhipidothuria
racowitzai) (Weddell Sea (epibenthic sledge), Antarctica).827
A Hainan Is. (South China Sea) collection of Bohadschia
marmorata yielded the hexaosides marmoratoside A 1028, 17ahydroxyimpatienside A 1029, marmoratoside B 1030 and
25-acetoxybivittoside D 1031.828 Moderate antifungal activities
were observed for 1028 and 1029.

This journal is The Royal Society of Chemistry 2011

The freeze-dried liposomal encapsulation of nobiliside A829


has been investigated,830 while semi-synthetic acetoxy derivatives of nobiloside B retain antitumour effects with reduced
haemolytic activity.831 Patagonicoside A832 and the desulfated
analogue exhibited modest levels of antiproliferative activity
towards human tumour cell lines, and promoted nuclear
translocation of NF-kB and degradation of inhibitory protein
IkBa.833 Both triterpene pentaosides frondoside A834 and
cucumarioside A2-2,835 induced apoptosis in leukemic cells, but
by differing mechanisms: cucumarioside A2-2 was caspasedependent, while frondoside A was caspase-independent.836
MS/MS techniques were used to investigate the saponin
chemistry of the body and Cuvierian tubules of a Mediterranean collection of Holothuria forskali.837 The Cuvierian
tubules, which act as a defensive organ, contained additional
saponins not found in the organism body wall. Structures for
a number of novel metabolites were proposed, but based solely
on MS/MS data. Surface-associated fatty acids and sterols,
including hexadecanoic acid, cholesterol, lathosterol and
sitosterol of the starfish Linckia laevigata, Fromia indica,
Cryptasterina pentagona and Archaster typicus, appear to
reduce settlement of fouling diatoms, bryozoa and polychaete
worms.838

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13 Mangroves and the intertidal zone


In the previous review,1 this section included compounds from
microorganisms isolated from mangroves and other sources in
the intertidal zone. For consistency, all reports for microorganisms from this region now appear in the marine microorganism
and phytoplankton section of this review. The structures of
macrocyclic polydisulfides 1032 and 1033, isolated from the
leaves and stems of the mangrove Bruguiera gymnorrhiza, were
secured.839 Extracts of the bark of Excoecaria agallocha (Hainan
Province, China) afforded the atisane diterpene 1034,840 in
addition to excoecarin V3, previously reported from the same
species.841 The latter natural product significantly inhibited
adherence of the biofilm-forming bacterium Pseudomonas pseudoalcaligenes.

Protoxylocarpins FH 10351037 were isolated as non-cytotoxic constituents of the seed kernels of Xylocarpus granatum
(Samutsongkram Province, Thailand).842 The absolute configuration at C-24 of 1035 was determined, while all other stereogenic centres were assigned as relative only.
A collection of seeds of X. granatum (Krishna Estuary,
Andhra Pradesh, India) yielded granatumins AG 10381044,843
while seeds of X. moluccensis, collected in the same locale, contained the C-30 keto-bearing moluccensins AG 10451051.844

14 Miscellaneous
The absolute configuration of ()-complanine, isolated from the
fireworm Eurythoe complanata,845 was determined by stereoselective synthesis from (R)-malic acid.846 Starting from D-

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proline, tandem sequences of olefination and Suzuki coupling


were used to confirm the structures and define absolute configurations of (+)-villatamines A and B,847 mildly cytotoxic alkaloids isolated from the flatworm Prostheceraeus villatus.848 A
trace alkaloidal constituent of the hoplonemertine marine worm
Amphiporus angulatus849 was determined to be 3-methyl-2,30 bipyridyl following synthesis of all eight possible isomers.850 An
11.7 kDa glycine-rich cysteine-containing peptide isolated from
the haemocytes of the spider crab Hyas araneus showed broadspectrum antimicrobial properties.851 The N-terminal region,
devoid of cysteines, exhibited attenuated bioactivity.

15 Conclusion
The value of natural products as a source of drug leads has been
well documented, with the majority of small-molecule pharmaceuticals across the disease spectrum being of natural product
origin, or natural product derived/inspired.852 Of the estimated
153,000 known natural products,853 22,000 are of marine
origin.66 Currently very few marine natural products have been or
are being developed into marketable drugs,5 and this may be
attributed in part to the fact that marine natural products have
a much shorter history of discovery than their terrestrial and
microbial counterparts. Furthermore, the major drug companies
have invested little effort into the development of natural product
leads over the past decade. However, it could be helpful to
compare the potential drug-likeness of marine natural products
with all other natural products, as measured by an examination of
their Lipinski characteristics, to determine whether there are any
features of marine compounds that might lead to them being
inherently more or less suitable as drug candidates. In 2008 Quinn
et al. analysed the drug-likeness of all the natural products,
including those of marine origin, as listed in the Dictionary of
Natural Products853 (DNP) (April, 2005; 126,140 unique
compounds)854 using the rule of five criterion described by
Lipinski.855 Briefly, this suggests that to be drug-like and orallybioavailable a molecule must have a partition coefficient (logP) <
5, a molecular weight <500 Da, <5 hydrogen bond donors (HBD)
and <10 hydrogen bond acceptors (HBA). By analyzing the
derived Lipinski data from this set, it was found that the molecular weight plot peaked in the 300400 Da range, clogP (calculated octanolwater logP) had a Gaussian distribution with
a maximum at 22.5, HBA peaked at 35 and then fell off rapidly,
while the HBD count rapidly fell from a maximum at 0. The
Lipinski data for a marine natural product selection (20,174
compounds), calculated using ACD algorithms,856 has now been
compared to those reported for the DNP selection. This analysis
shows great similarity between the two data sets. The most
significant difference however was in the distribution of the clogP
values for the marine compounds that had a maximum between 4
and 5, suggesting a greater average lipophilicity of the marine
compounds. This skewing of the clogP distribution to higher
values is not favourable in terms of bioavailability, but clogP
values are not considered entirely reliable, especially with Br
substituents.854 When the Lipinski violations were compared for
the marine vs. the DNP compound sets there was a marked
change in distribution (see Fig. 1), with only 42% of all marine
metabolites having zero Lipinski violations. However, the relative
proportion of compounds having zero or one violations of
This journal is The Royal Society of Chemistry 2011

Fig. 1 Lipinski violations for marine natural products (blue) and all
natural products (red).

Lipinskis rule of five was closer (74% vs. 80%). The broad
conclusion that can be drawn from this very simple analysis of the
general physico-chemical properties of marine natural products is
that they too are Lipinski-worthy, and in the future they should
be a source of many more small-molecule pharmaceuticals.
An aim of the rule of five was to highlight bioavailability
problems based on calculable physico-chemical parameters. In
Fig. 2 the major marine phyla explored to date (each having >2%
of all compounds isolated) are compared on the basis of zero or
one Lipinski violation.
The analysis given in Fig. 2 highlights the lipophilicity of many
of the compounds in the phyla examined, particularly for the
Ochrophyta, Porifera, Mollusca and Cnidaria. Given the overall
importance of logP to permeability and bioavailability, any
conclusions that could be drawn from Fig. 2 about any particular
phylum being a source of compounds with fewer Lipinski violations should be made with caution. More recently, simple rules
that have been derived from an extensive analysis of ADMET
(adsorption, distribution, metabolism, excretion and toxicity)
parameters highlight the role of MW and clogP.857 Increasing
values in either MW or clogP are generally detrimental to more
than one ADMET parameter. As a consequence it was suggested
that a molecule has more desirable oral-bioavailability physicochemical properties if MW < 400 and clogP < 4. An analysis of
the marine natural products data based on these parameters is
shown in Fig. 3, and suggests that the Actinobacteria and Ascomycota have a greater proportion of compounds that meet these
criteria. These two phyla were also distinctive in the analysis
shown in Fig. 2. Physico-chemical parameters can suggest the
optimum combinations for potential pharmaceuticals, but the
real test is placing purified compounds into biological testing, or
implementing a bioassay-guided approach to selection. Ultimately, however, the potential of a marine natural product as
a drug candidate will be determined by the biological evaluation
results, not the calculated physico-chemical parameters.
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Fig. 2 Lipinski violations as a function of phylum: the total height of


each bar is the sum of zero and one violations for that phylum. The %
contributions are shown for zero violations (blue), one violation (but not
clogP) (red) and the contribution from a clogP violation (green).

Fig. 3 Analysis of marine natural products having MW < 400 and


clogP < 4.

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